PMC:7556165 / 44914-49334 JSONTXT

{"project":"LitCovid-sample-MedDRA","denotations":[{"id":"T79","span":{"begin":522,"end":532},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"},{"id":"T80","span":{"begin":908,"end":920},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"},{"id":"T81","span":{"begin":945,"end":950},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"},{"id":"T82","span":{"begin":2030,"end":2042},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"},{"id":"T83","span":{"begin":2524,"end":2536},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"},{"id":"T84","span":{"begin":3932,"end":3945},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"}],"attributes":[{"id":"A84","pred":"meddra_id","subj":"T84","obj":"http://purl.bioontology.org/ontology/MEDDRA/10050417"},{"id":"A82","pred":"meddra_id","subj":"T82","obj":"http://purl.bioontology.org/ontology/MEDDRA/10062026"},{"id":"A83","pred":"meddra_id","subj":"T83","obj":"http://purl.bioontology.org/ontology/MEDDRA/10062026"},{"id":"A80","pred":"meddra_id","subj":"T80","obj":"http://purl.bioontology.org/ontology/MEDDRA/10062026"},{"id":"A79","pred":"meddra_id","subj":"T79","obj":"http://purl.bioontology.org/ontology/MEDDRA/10069374"},{"id":"A81","pred":"meddra_id","subj":"T81","obj":"http://purl.bioontology.org/ontology/MEDDRA/10048064"}],"text":"SARS-CoV-2 RBD and Its Receptor, ACE2\nSince SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV. SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

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The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

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RBD and Its Receptor, ACE2\nSince SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV. SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

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SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

{"project":"LitCovid-sample-PD-UBERON","denotations":[{"id":"T139","span":{"begin":3405,"end":3418},"obj":"Body_part"}],"attributes":[{"id":"A139","pred":"uberon_id","subj":"T139","obj":"http://purl.obolibrary.org/obo/UBERON_0002405"}],"text":"SARS-CoV-2 RBD and Its Receptor, ACE2\nSince SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV. SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

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RBD and Its Receptor, ACE2\nSince SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV. SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

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RBD and Its Receptor, ACE2\nSince SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV. SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

{"project":"LitCovid-sample-PD-IDO","denotations":[{"id":"T185","span":{"begin":83,"end":87},"obj":"http://purl.obolibrary.org/obo/IDO_0000531"},{"id":"T186","span":{"begin":88,"end":92},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T187","span":{"begin":625,"end":629},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T188","span":{"begin":645,"end":650},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T189","span":{"begin":834,"end":839},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T190","span":{"begin":2920,"end":2925},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T191","span":{"begin":3426,"end":3430},"obj":"http://purl.obolibrary.org/obo/IDO_0000531"},{"id":"T192","span":{"begin":3743,"end":3747},"obj":"http://purl.obolibrary.org/obo/IDO_0000531"},{"id":"T193","span":{"begin":3865,"end":3869},"obj":"http://purl.obolibrary.org/obo/IDO_0000531"},{"id":"T194","span":{"begin":3870,"end":3875},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T195","span":{"begin":3946,"end":3952},"obj":"http://www.geneontology.org/formats/oboInOwl#Subset"}],"text":"SARS-CoV-2 RBD and Its Receptor, ACE2\nSince SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV. SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

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X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

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RBD and Its Receptor, ACE2\nSince SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV. SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

{"project":"LitCovid-sample-Glycan","denotations":[{"id":"T14","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G02780QX"},{"id":"T15","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G18425DX"},{"id":"T16","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G18630JE"},{"id":"T17","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G87301QZ"},{"id":"T18","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G01004IT"},{"id":"T19","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G39790GW"},{"id":"T20","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G68183GR"},{"id":"T21","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G42928BB"},{"id":"T22","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G51134HC"},{"id":"T23","span":{"begin":2451,"end":2454},"obj":"https://glytoucan.org/Structures/Glycans/G54702VY"}],"text":"SARS-CoV-2 RBD and Its Receptor, ACE2\nSince SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV. SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

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RBD and Its Receptor, ACE2\nSince SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV. SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020). In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.\nFIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue. The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A). The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020). Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a). This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host. Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases. Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}

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SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005). Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020). Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy. Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor). Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.\nThe SARS-CoV-2 RBD sequence was further investigated by structural analysis. 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The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website. Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2. Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD. To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch. In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1). Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b). In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020). 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Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.\nTABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.\nSequence KD (nM) Method References\nSARS-2 S 14.7 SPR Wrapp et al., 2020\nSARS-2 S 11.2 SPR Lei et al., 2020\nSARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020\nSARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020\nSARS-2 S319–529 44.2 SPR Shang et al., 2020b\nSARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020\nSARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020"}