CORD-19-Sentences  

CORD-19:12af81d8d81c5da78255316d73ab6564cc2e835e JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-25 Sentence denotes Viruses and Sialic Acids:
TextSentencer_T2 26-45 Sentence denotes Rules of Engagement
TextSentencer_T3 47-55 Sentence denotes Abstract
TextSentencer_T4 56-175 Sentence denotes Viral infections are initiated by specific attachment of a virus particle to receptors at the surface of the host cell.
TextSentencer_T5 176-269 Sentence denotes For many viruses, these receptors are glycans that are linked to either a protein or a lipid.
TextSentencer_T6 270-409 Sentence denotes Glycans terminating in sialic acid and its derivatives serve as receptors for a large number of viruses, including several human pathogens.
TextSentencer_T7 410-604 Sentence denotes In combination with glycan array analyses, structural analyses of complexes of viruses with sialylated oligosaccharides have provided insights into the parameters that underlie each interaction.
TextSentencer_T8 605-736 Sentence denotes Here, we compare the currently available structural data on viral attachment proteins in complex with sialic acid and its variants.
TextSentencer_T9 737-873 Sentence denotes The objective is to define common parameters of recognition and to provide a platform for understanding the determinants of specificity.
TextSentencer_T10 874-1032 Sentence denotes This information could be of use for the prediction of the location of sialic acid binding sites in viruses for which structural information is still lacking.
TextSentencer_T11 1033-1217 Sentence denotes An improved understanding of the principles that govern the recognition of sialic acid and sialylated oligosaccharides would also advance efforts to develop efficient antiviral agents.
TextSentencer_T12 1219-1403 Sentence denotes The monosaccharide sialic acid decorates all eukaryotic cell surfaces, capping many different oligosaccharide structures on N-and O-linked glycoproteins as well as on glycolipids [1] .
TextSentencer_T13 1404-1551 Sentence denotes Glycans terminating in sialic acid have emerged as a key class of receptors for an impressive number of viruses, many of which are human pathogens.
TextSentencer_T14 1552-1695 Sentence denotes The highly pathogenic Influenza A, B and C viruses as well as the human parainfluenzaviruses attach to sialic acids (reviewed in [2] [3] [4] ).
TextSentencer_T15 1696-1868 Sentence denotes Coxsackievirus A24 variant and Enterovirus 70, which cause Acute Hemorrhagic Conjunctivitis and have pandemic potential, also attach to sialylated oligosaccharides [5, 6] .
TextSentencer_T16 1869-2046 Sentence denotes Epidemic Keratoconjunctivitis (EKC) has been linked to several human D-type Adenoviruses, and one of these has recently been shown to attach to the disialylated GD1a motif [7] .
TextSentencer_T17 2047-2216 Sentence denotes The human JC and BK Polyomaviruses (JCV and BKV, respectively) cause a fatal demyelinating disease and kidney graft loss, respectively, in immunocompromised individuals.
TextSentencer_T18 2217-2296 Sentence denotes Both viruses use glycans terminating in sialic acid as their receptors [8, 9] .
TextSentencer_T19 2297-2609 Sentence denotes Moreover, the recently identified Merkel Cell Polyomavirus, a human oncovirus, likely uses the trisialylated ganglioside GT1b as a receptor [10, 11] , and other mammalian polyomaviruses such as Simian Virus 40 (SV40) and murine Polyomavirus (Polyoma) also bind glycans terminating in sialic acid [12] [13] [14] .
TextSentencer_T20 2610-2830 Sentence denotes Most human noroviruses, the causative agents of violent gastrointestinal illnesses, attach to non-sialylated histo-blood group antigens, in contrast to murine norovirus, which binds to a sialylated oligosaccharide [15] .
TextSentencer_T21 2831-2944 Sentence denotes However, some strains of human noroviruses were recently shown to bind to the sialyl-Lewis X motif as well [16] .
TextSentencer_T22 2945-2998 Sentence denotes Rotaviruses cause severe gastroenteritis in children.
TextSentencer_T23 2999-3203 Sentence denotes They have long been classified into strains that can be inhibited by neuraminidase treatment, which cleaves sialic acid from glycan sequences on host cells, and those that are insensitive to it [17, 18] .
TextSentencer_T24 3204-3284 Sentence denotes Neuraminidase-insensitive strains were presumed to use non-sialylated receptors.
TextSentencer_T25 3285-3449 Sentence denotes Interestingly, the "neuraminidase-insensitive" rotavirus strain Wa was recently shown to attach to the ganglioside GM1, which carries a branching sialic acid [19] .
TextSentencer_T26 3450-3563 Sentence denotes Due to its branched structure, this particular carbohydrate is difficult to cleave with neuraminidases [20, 21] .
TextSentencer_T27 3564-3702 Sentence denotes SV40 had likewise been presumed to attach to a non-sialylated carbohydrate [22] [23] [24] before GM1 was identified as its receptor [12] .
TextSentencer_T28 3703-3890 Sentence denotes Sialic acid therefore has to be considered as a possible receptor component even for viruses whose infectivity cannot be modulated by treatment of cells with commonly used neuraminidases.
TextSentencer_T29 3891-4086 Sentence denotes The structure of the most common sialic acid in humans, α-5-N-acetyl-neuraminic acid (Neu5Ac), features four protruding functional groups (carboxylate, hydroxyl, N-acetyl and glycerol functions).
TextSentencer_T30 4087-4287 Sentence denotes Compared to more simple monosaccharides, the large number of functional groups enables sialic acids to participate in an unparalleled number of hydrogen bonds, salt bridges and non-polar interactions.
TextSentencer_T31 4288-4409 Sentence denotes Since sialic acid is typically located at the terminus of a glycan, its functions are easily accessible for interactions.
TextSentencer_T32 4410-4739 Sentence denotes Perhaps it is not surprising, therefore, that the sialic acid itself serves as the major point of contact with the glycan-binding viral attachment protein in all cases where structural information of sufficient resolution is available [8, 13, [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] .
TextSentencer_T33 4740-4971 Sentence denotes In this review, we compare binding modes of sialic acids and sialylated receptors in representative structures of virus-receptor complexes in order to derive parameters that guide the recognition of sialic acid and its derivatives.
TextSentencer_T34 4972-5181 Sentence denotes Such parameters could be useful for the prediction of new sialic acid binding sites in viral proteins, or of altered modes of sialic acid (and its derivatives) binding in different viral serotypes and strains.
TextSentencer_T35 5182-5403 Sentence denotes Several structures of viral attachment proteins in complex with sialylated compounds have been determined recently, providing new insights into viral specificity for glycan receptors [8, 13, [35] [36] [37] [38] [39] 41] .
TextSentencer_T36 5404-5635 Sentence denotes Taken together, the known structures now form a large database that is suitable for the closer examination of contacts in order to compare the modes of interaction and attempt to define common principles of sialic acid recognition.
TextSentencer_T37 5636-6211 Sentence denotes We have investigated here the mode of Neu5Ac binding for nine different viral attachment proteins ( Fig. 1 ): the hemagglutinins (HAs) of Influenza A and B viruses [26, 34] , the Adenovirus serotype 37 (Ad37) fiber knob [7] , the canine Adenovirus serotype 2 (cAd2) fiber knob [39] , the major capsid proteins VP1 of the polyomaviruses Polyoma [29] , SV40 [13] , and JCV [8] , the attachment protein σ1 of human type 3 orthoreovirus [41] , the attachment protein VP8* of Rhesus Rotavirus [30] , and the hemagglutinin-neuraminidase (HN) of Newcastle Disease Virus (NDV) [31] .
TextSentencer_T38 6212-6386 Sentence denotes As the interactions with terminal sialic acid are very similar among different types of Influenza A HAs, the structure of the H3 type [26] was chosen to represent this group.
TextSentencer_T39 6387-6662 Sentence denotes In addition, we have also analyzed contacts in the hemagglutinin-esterase-fusion (HEF) protein of Influenza C virus [27] and the hemagglutinin-esterase (HE) proteins of Bovine Coronavirus (BCoV) [35] , Bovine Torovirus (BToV) [36] and Porcine Torovirus (PToV) [36] (Fig. 2) .
TextSentencer_T40 6663-6772 Sentence denotes These four proteins bind to derivatives of Neu5Ac that are Oacetylated at position 9 or at positions 4 and 9.
TextSentencer_T41 6773-7065 Sentence denotes In cases where the attachment protein also has receptor-destroying enzymatic activity, such as in the HN and HE(F) proteins, only the sites that can clearly be attributed to attachment are considered here, thus excluding the dual function neuraminidase site of some HN proteins [32, 42, 43] .
TextSentencer_T42 7066-7245 Sentence denotes The investigated viral attachment proteins are, for the most part, not homologous to one another and belong to unrelated viruses that differ in envelope structure and genome type.
TextSentencer_T43 7246-7332 Sentence denotes Nevertheless, their interactions with sialic acid display striking similarities (Figs.
TextSentencer_T44 7333-7340 Sentence denotes 1, 2) .
TextSentencer_T45 7341-7564 Sentence denotes In all complexes, the sialic acid adopts essentially the same conformation, namely a trans conformation of the 5-N-acetyl group and an α-conformation at the anomeric carbon, which is dominant in biological oligosaccharides.
TextSentencer_T46 7565-7783 Sentence denotes Interestingly, all attachment proteins, including the ones that bind to O-acetylated compounds, make extensive contacts with one face of the sialic acid ring, while the other face is engaged by only few contacts (Figs.
TextSentencer_T47 7784-7794 Sentence denotes 1A, 2A-C).
TextSentencer_T48 7795-7921 Sentence denotes A likely reason for this preference is the formation of two key contacts that are formed in all complexes in a similar manner.
TextSentencer_T49 7922-8074 Sentence denotes One of these contacts involves the negatively charged carboxylate group, which is most often recognized by two parallel hydrogen bonds or a salt bridge.
TextSentencer_T50 8075-8169 Sentence denotes Each of the analyzed proteins donates at least one hydrogen bond to a carboxylate oxygen atom.
TextSentencer_T51 8170-8238 Sentence denotes The second contact involves the nitrogen atom in the N-acetyl group.
TextSentencer_T52 8239-8325 Sentence denotes With only one exception, all proteins receive a hydrogen bond from this nitrogen atom.
TextSentencer_T53 8326-8457 Sentence denotes The spatial arrangement of carboxyl group and the N-acetyl nitrogen thus helps distinguish sialic acids from other monosaccharides.
TextSentencer_T54 8458-8597 Sentence denotes Both groups project from the same face of the sialic acid ring, accounting for the preferential binding of this face of the monosaccharide.
TextSentencer_T55 8598-8795 Sentence denotes Apart from these two key interactions, the proteins engage in different hydrogen bonding patterns to various hydroxyl groups of the glycerol chain or the ring, or to additional acetyl substituents.
TextSentencer_T56 8796-8900 Sentence denotes Neu5Ac reveals that only about 50% of the contact surface of Neu5Ac participates in such contacts (Figs.
TextSentencer_T57 8901-8909 Sentence denotes 1A, 2C).
TextSentencer_T58 8910-9025 Sentence denotes The resulting shape resembles a rimmed imprint of the binding face of Neu5Ac on the protein surface (Fig. 1A, 2C ).
TextSentencer_T59 9026-9126 Sentence denotes In all complexes, van der Waals interactions are formed with the methyl group of the N-acetyl chain.
TextSentencer_T60 9127-9239 Sentence denotes However, the different proteins interacting with Neu5Ac sample different epitopes on the Neu5Ac contact surface.
TextSentencer_T61 9240-9408 Sentence denotes For example, JCV and SV40 VP1, Rhesus Rotavirus VP8*, and Influenza A HA all center their van der Waals contacts on the glycerol and N-acetyl chains (Fig 1E, F , I, J).
TextSentencer_T62 9409-9554 Sentence denotes The surfaces of all four viruses feature subtle protrusions that separate the recessed areas in which the glycerol and N-acetyl chains are bound.
TextSentencer_T63 9555-9695 Sentence denotes Polyoma VP1, on the other hand, mainly contacts Neu5Ac from the other side, and does not interact with the glycerol chain at all (Fig. 1B) .
TextSentencer_T64 9696-9828 Sentence denotes Examination of the binding surfaces demonstrates that shape complementarity is an important factor in the engagement of sialic acid.
TextSentencer_T65 9829-10056 Sentence denotes As the contact areas are quite small and the sialic acids are partially exposed to solvent, adding or removing a single contact can thus have significant effects on the affinity of a given virus for sialic acid or its variants.
TextSentencer_T66 10057-10213 Sentence denotes The parent compound of Neu5Ac, neuraminic acid, can feature numerous modifications that give rise to over 40 different known sialic acid variants [44, 45] .
TextSentencer_T67 10214-10328 Sentence denotes Several of these modifications are predominantly found on specific cell types and tissues, or in selected species.
TextSentencer_T68 10329-10472 Sentence denotes It is perhaps not surprising, therefore, that some viruses exploit this divergence and preferentially recognize sialic acids other than Neu5Ac.
TextSentencer_T69 10473-10652 Sentence denotes The database of viral protein structures contains few examples of viruses attaching to O-acetylated Neu5Ac [27, 35, 36] , but their analysis is nevertheless informative (Fig. 2) .
TextSentencer_T70 10653-10814 Sentence denotes While the key hydrogen bonds to one face of the sialic acid are the same as described for Neu5Ac, the distribution of van der Waals contacts is somewhat altered.
TextSentencer_T71 10815-11065 Sentence denotes In the four complexes, the majority of van der Waals contacts are centered around the unique 9-O-acetyl groups as well as the adjacent side of the N-acetyl group, while the opposite side of the ring does not engage in as many interactions (Fig. 2B) .
TextSentencer_T72 11066-11202 Sentence denotes The 9-O-acetyl group inserts deeply into tight-fitting protein cavities, providing selectivity for sialic acids modified in this manner.
TextSentencer_T73 11203-11301 Sentence denotes Recognition of different sialic acids is also a likely cause of changes in tropism and host range.
TextSentencer_T74 11302-11477 Sentence denotes The interactions of SV40 with GM1 ganglioside containing α-N-5-glycolyl neuraminic acid (Neu5Gc), a sialic acid present in simians but not humans, illustrate this point [46] .
TextSentencer_T75 11478-11675 Sentence denotes SV40 VP1 features a large pocket near the Neu5Ac N-acetyl group (Fig. 1F, 3B) , and it is tempting to speculate that this pocket serves to accommodate the additional hydroxyl group of Neu5Gc [13] .
TextSentencer_T76 11676-11883 Sentence denotes VP1 of the human JCV (Fig. 1E, 3A) , whose sialic acid binding site is largely similar to that of SV40 VP1, features a much smaller pocket that likely prefers the smaller human Neu5Ac over the simian Neu5Gc.
TextSentencer_T77 11884-11959 Sentence denotes Sialic acid binding sites are often highly conserved in homologous viruses.
TextSentencer_T78 11960-12127 Sentence denotes This is evident when comparing different HA types of Influenza A, the capsid proteins of JCV and SV40 (Fig. 3A, B) , or the HE proteins of PToV and BToV (Fig. 2F, G) .
TextSentencer_T79 12128-12283 Sentence denotes In all three cases, the sialic acid engages the two homologous proteins using similar contacts and is therefore bound in the same orientation and position.
TextSentencer_T80 12284-12433 Sentence denotes However, at least one example exists where homologous proteins, the Ad37 and cAd2 fiber knobs, bind sialic acid at different locations (Fig. 1C, D) .
TextSentencer_T81 12434-12575 Sentence denotes Interestingly, there are several examples of highly homologous proteins that bind sialic acid at the same site but in different orientations.
TextSentencer_T82 12576-12751 Sentence denotes The VP1 proteins of Polyoma and SV40, for example, feature a very high level of sequence identity, and they bind sialic acid in generally similar areas on the protein surface.
TextSentencer_T83 12752-12839 Sentence denotes However, the orientations of the bound sialic acids differ markedly (Fig. 1B, F) [13] .
TextSentencer_T84 12840-13062 Sentence denotes Similarly, Influenza C HEF and BCoV HE bind sialic acid at the same position, but again in different orientations with respect to the proteins and with contacts provided by different structural elements (Fig. 2D, E) [35] .
TextSentencer_T85 13063-13191 Sentence denotes These two examples demonstrate the need for caution when modeling interactions with sialic acid based on a homologous structure.
TextSentencer_T86 13192-13342 Sentence denotes As sialic acid is ubiquitous at the cell surface, interactions with subsequent carbohydrates are typically employed to define specificity and tropism.
TextSentencer_T87 13343-13443 Sentence denotes Glycan microarrays have been highly useful in revealing the determinants of such interactions [47] .
TextSentencer_T88 13444-13694 Sentence denotes The critical role of the context of the sialic acid -linkage type, as well as length, sequence and conformational preferences of the remaining oligosaccharide chain -is perhaps best illustrated by its influence on the host range of Influenza viruses.
TextSentencer_T89 13695-13910 Sentence denotes Briefly, human Influenza A viruses engage long glycans terminating in α2,6-linked sialic acid that preferentially adopt a bent conformation and that are expressed extensively in the upper airway epithelia of humans.
TextSentencer_T90 13911-14058 Sentence denotes Avian strains predominantly recognize shorter glycans that adopt a linear conformation and that often contain α2,3-linked linked sialic acid [48] .
TextSentencer_T91 14059-14297 Sentence denotes The vast database on Influenza A HA structures in complex with sialylated ligands, and concurrent glycan array analyses, has been the subject of several excellent recent reviews [2, 3] , and will therefore not be discussed in detail here.
TextSentencer_T92 14298-14521 Sentence denotes However, glycan array screening has recently helped to unravel the identities of sialylated glycan receptors for two pathogenic human viruses, and structural biology has defined the nature of interaction in both cases [8] .
TextSentencer_T93 14522-14657 Sentence denotes We review below each of these two examples, which illuminate the importance of the context in which the terminal sialic acid is placed.
TextSentencer_T94 14658-14746 Sentence denotes Several members of the polyomavirus family use sialylated receptors for cell attachment.
TextSentencer_T95 14747-15136 Sentence denotes Crystal structures of two members of the family in complex with their cognate receptors have been determined recently: SV40 VP1 has been crystallized in complex with the oligosaccharide portion of its ganglioside receptor GM1 [13] , whereas the structure of the VP1 protein of human JCV has been solved with the pentasaccharide receptor fragment LSTc (Lacto-series tetrasaccharide c) [8] .
TextSentencer_T96 15137-15282 Sentence denotes Both receptors feature terminal Neu5Ac, which is α2,3-linked in the branched GM1 molecule and α2,6-linked in the linear LSTc structure (Fig. 3) .
TextSentencer_T97 15283-15383 Sentence denotes In each case, glycan array screening has unequivocally identified the type of the receptor [13, 8] .
TextSentencer_T98 15384-15540 Sentence denotes Moreover, although both GM1 and LSTc were present on the arrays, JCV VP1 failed to interact with GM1, and SV40 VP1 also did not recognize the LSTc compound.
TextSentencer_T99 15541-15609 Sentence denotes Thus, both proteins are highly specific for their cognate receptors.
TextSentencer_T100 15610-15792 Sentence denotes A comparison of the two structures shows that the sialic acid portions of the two receptors form largely equivalent interactions with their respective proteins (Fig. 1E, F; Fig. 3 ).
TextSentencer_T101 15793-15925 Sentence denotes The remarkable specificity for each receptor can be attributed to contacts that involve the remaining parts of the oligosaccharides.
TextSentencer_T102 15926-16078 Sentence denotes The LSTc compound assumes a bent conformation, forming additional contacts via the N-acetyl group of its third sugar, GlcNAc, to N123 of JCV (Fig. 3A ).
TextSentencer_T103 16079-16264 Sentence denotes An α2,3-linked Neu5Ac would not adopt a similarly bent conformation, explaining why sialylparagloboside, which is identical to LSTc except for its α2,3-linked Neu5Ac, does not bind JCV.
TextSentencer_T104 16265-16404 Sentence denotes Modeling LSTc into the SV40 VP1 binding site by superimposing the two sialic acid structures suggests that LSTc could be tolerated by SV40.
TextSentencer_T105 16405-16556 Sentence denotes However, as the residue equivalent to N123 in JCV is a glycine (G131) in SV40, no favorable contacts to the GlcNAc residue can be generated (Fig. 3B) .
TextSentencer_T106 16557-16646 Sentence denotes The inability to form such an interaction most likely explains why SV40 cannot bind LSTc.
TextSentencer_T107 16647-16790 Sentence denotes It therefore appears that the formation of a very small number of contacts is largely responsible for defining the specificity of VP1 for LSTc.
TextSentencer_T108 16791-16946 Sentence denotes The reverse combination, a GM1 ligand bound to JCV, would likely be disfavored due to steric clashes with JCV VP1 residue S62, which is an alanine in SV40.
TextSentencer_T109 16947-17209 Sentence denotes Due to their small contact surfaces and solvent-exposed binding sites, interactions between individual viral attachment proteins and sialylated oligosaccharides are typically of low affinity, with dissociation constants in the millimolar range [13, 28, 49, 50] .
TextSentencer_T110 17210-17342 Sentence denotes In many cases, high-affinity adherence to the target cell is achieved through the utilization of several low affinity binding sites.
TextSentencer_T111 17343-17431 Sentence denotes However, receptor clustering is not always necessary to achieve higher-affinity binding.
TextSentencer_T112 17432-17535 Sentence denotes The interaction of Ad37 with its recently identified glycan receptor GD1a illustrates another strategy.
TextSentencer_T113 17536-17690 Sentence denotes It has long been established that Ad37 fiber knobs bind receptors terminating in sialic acid [28, 51] , but the nature of the glycan has remained elusive.
TextSentencer_T114 17691-17896 Sentence denotes Glycan array screening has recently revealed that Ad37 fiber knobs specifically recognize the oligosaccharide GD1a, a disialylated compound that features two branches, each terminating in sialic acid [7] .
TextSentencer_T115 17897-18167 Sentence denotes A structural analysis of the trimeric Ad37 fiber knob in complex with GD1a established that the two terminal sialic acid residues bind to two different Ad37 fiber knob protomers in an identical manner, thus engaging two of the three possible binding sites [7] (Fig. 4) .
TextSentencer_T116 18168-18330 Sentence denotes This bivalent interaction results in a 250-fold higher affinity (Kd = 19 μM) [7] compared to the monovalent sialyllactose-Ad37 knob interaction (Kd = 5 mM) [28] .
TextSentencer_T117 18331-18607 Sentence denotes Thus, although each protomer in an Ad37 fiber knob would be able to bind sialic acid attached to different oligosaccharide structures, specificity for GD1a is generated by a multivalent interaction in which two protomers interact with the same receptor in an identical manner.
TextSentencer_T118 18608-18814 Sentence denotes It is conceivable that trivalent compounds that engage all three binding sites of the Ad37 fiber knobs would have even higher affinity, thus providing a platform for the development of antiviral inhibitors.
TextSentencer_T119 18815-18969 Sentence denotes Using such a strategy, a multivalent inhibitor has been developed that is able to neutralize pentameric shiga-like toxins with very high efficiency [52] .
TextSentencer_T120 18970-19120 Sentence denotes A similar strategy could be useful to develop molecules that inhibit viral attachment proteins, which usually occur as multimers at the viral surface.
TextSentencer_T121 19121-19241 Sentence denotes A large number of viruses, including many serious human pathogens, uses sialylated oligosaccharides for cell attachment.
TextSentencer_T122 19242-19358 Sentence denotes Common principles of interaction can be established by comparing the sialic acid binding modes of different viruses.
TextSentencer_T123 19359-19583 Sentence denotes In most cases, interactions between a viral attachment protein and its glycan receptor involve primarily the sialic acid itself, which is bound with a relatively small contact area in a solvent-exposed region of the protein.
TextSentencer_T124 19584-19705 Sentence denotes Consistent with this, the affinities of such interactions are, at least in cases where they have been measured, very low.
TextSentencer_T125 19706-20009 Sentence denotes Nevertheless, many of the viruses discussed here achieve remarkable specificity for a single type of sialylated oligosaccharide by establishing a small number of auxiliary interactions with functional groups that lie beyond the sialic acid, and by excluding some possible ligands through steric clashes.
TextSentencer_T126 20010-20178 Sentence denotes The auxiliary interactions generally involve fewer hydrogen bonds and bury a smaller amount of surface compared to the interactions that involve the sialic acid itself.
TextSentencer_T127 20179-20428 Sentence denotes It thus appears that many viruses use the unique properties of sialic acid as a "hook" that allows them to adhere to the cell, and modulate binding in different strains or families by subtly altering structural elements in the vicinity of this hook.
TextSentencer_T128 20429-20702 Sentence denotes In a (so far) unique variation of this strategy, the Ad37 knob establishes selectivity for its GD1a glycan receptor by multivalent binding to a single receptor carrying two terminal sialic acid moieties, thus adhering to two identical "hooks" separated by a defined spacer.
TextSentencer_T129 20703-20807 Sentence denotes The prominence of sialic acid in viral attachment may form a basis for new approaches to combat viruses.
TextSentencer_T130 20808-21028 Sentence denotes Compounds that mimic sialic acid have already proved useful as inhibitors of the Influenza virus neuraminidase [53] and can also efficiently inhibit the receptor-binding site of the Influenza A virus hemagglutinin [54] .
TextSentencer_T131 21029-21213 Sentence denotes The structural analysis of the Ad37-GD1a interaction has also led to the design and synthesis of a trivalent compound designed to block attachment of adenoviruses that cause EKC [55] .
TextSentencer_T132 21214-21392 Sentence denotes Glycan microarrays have been extraordinarily useful in identifying the correct receptors for many viral proteins [8, 13, 47, 56] , which is a prerequisite for structural studies.
TextSentencer_T133 21393-21525 Sentence denotes However, proper interpretation of the information provided by glycan array screening and structural analyses requires affinity data.
TextSentencer_T134 21526-21629 Sentence denotes Such data are often difficult to obtain and compare, and they are currently lacking for many complexes.
TextSentencer_T135 21630-21847 Sentence denotes Being able to correlate affinity measurements with structural data would significantly advance the design of antiviral agents, and, together with oligosaccharide expression data, help to explain viral tropism. [34] ).
TextSentencer_T136 21848-21928 Sentence denotes In all cases, Neu5Ac is shown in stick representation and colored as in panel A.
TextSentencer_T137 21929-22059 Sentence denotes The protein surfaces are colored gray, with residues interacting with Neu5Ac shown in stick representation and colored by element.
TextSentencer_T138 22060-22147 Sentence denotes Protein atoms within a 4.0 Å radius around Neu5Ac are highlighted with colored spheres.
TextSentencer_T139 22148-22266 Sentence denotes In cases where the Neu5Ac binding site is formed by two protein chains, one of the chains is denoted with an asterisk.
TextSentencer_T140 22267-22388 Sentence denotes The oligosaccharides are shown in stick representation and colored by element, with oxygens in red and nitrogens in blue.
TextSentencer_T141 22389-22535 Sentence denotes Monosaccharides that approach the protein closer than 4.0 Å are colored in bright orange, while those not contacting the protein are colored gray.
TextSentencer_T142 22536-22627 Sentence denotes Oligosaccharide atoms within a 4.0 Å radius around the proteins are highlighted as spheres.
TextSentencer_T143 22628-22665 Sentence denotes The protein surface is shown in gray.
TextSentencer_T144 22666-22832 Sentence denotes Residues that define the different oligosaccharide specificities of the two proteins are shown as sticks and colored blue and pink for SV40 and JCV VP1, respectively.
TextSentencer_T145 22833-22912 Sentence denotes Residues from a different polypeptide chain are denoted with an asterisk. [7] .
TextSentencer_T146 22913-23036 Sentence denotes The three different Ad37 fiber knob protomers are shown in surface representation and are colored gray, light red and blue.
TextSentencer_T147 23037-23192 Sentence denotes The GD1a glycan is drawn in stick representation, with both Neu5Ac residues highlighted in color (carbons in orange, oxygens in red and nitrogens in blue).
TextSentencer_T148 23193-23245 Sentence denotes The bridging glycan residues are shown in dark gray.
TextSentencer_T149 23246-23320 Sentence denotes The third binding site (marked by "X") is blocked due to crystal contacts.
TextSentencer_T150 23321-23385 Sentence denotes The arrow indicates the viewing direction shown in panel B. (B).
TextSentencer_T151 23386-23441 Sentence denotes Interactions between Ad37 fiber knob residues and GD1a.
TextSentencer_T152 23442-23552 Sentence denotes Two different Ad37 fiber knob protomers are shown in transparent surface representation (white and light red).
TextSentencer_T153 23553-23597 Sentence denotes The third protomer is not shown for clarity.
TextSentencer_T154 23598-23705 Sentence denotes Ad37 residues contacting GD1a are shown in stick representation, with oxygens in red and nitrogens in blue.
TextSentencer_T155 23706-23870 Sentence denotes The GD1a glycan is shown in stick representation, with both terminal Neu5Ac residues highlighted in color (carbons in orange, oxygens in red and nitrogens in blue).
TextSentencer_T156 23871-23918 Sentence denotes The bridging glycan residues are shown in gray.
TextSentencer_T157 23919-24000 Sentence denotes Glycan atoms within a distance of 4 Å to Ad37 protein atoms are drawn as spheres.
TextSentencer_T158 24001-24065 Sentence denotes Hydrogen bonds to GD1a glycan are represented with black dashes.
TextSentencer_T159 24066-24129 Sentence denotes Residues from different protomers are denoted with an asterisk.