PMC:4504005 / 15153-17680 JSONTXT

{"project":"TEST0","denotations":[{"id":"25982113-87-95-8319020","span":{"begin":160,"end":164},"obj":"[\"20826335\", \"20826335\", \"20826335\"]"},{"id":"25982113-79-87-8319021","span":{"begin":900,"end":904},"obj":"[\"20826335\", \"20826335\", \"20826335\"]"},{"id":"25982113-82-90-8319022","span":{"begin":1687,"end":1691},"obj":"[\"22102369\", \"22102369\", \"22102369\"]"}],"text":"Comparisons to Ligand-free and Small Molecule Antagonist-Bound Structures\nSuperpositions of CGRPmut-bound and ligand-free CLR:RAMP1 complexes (ter Haar et al., 2010) revealed clamp-like movement of CLR loops 3 and 4 upon CGRPmut binding, presumably mediated by the CGRPmut T30-CLR D94 interaction and β-turn contacts with CLR loop 4 including the CGRPmut F35-CLR S117 interaction (Figures 3A and 3B). CLR R119 shifts to accommodate the peptide and RAMP1 F83 rotates away from CLR loop 4 (Figure 3B). The RAMP1 position relative to CLR varies in the structures (Figure 3A), but the positions of the α2-α3 loop and W84, which contacts CGRPmut F37, remain relatively similar (Figures 3A and 3B).\nThe CGRPmut-bound structure explains antagonism by the CGRP receptor-selective small molecule drugs olcegepant and telcagepant. Superposition of the CGRPmut-bound and drug-bound structures (ter Haar et al., 2010) indicated that olcegepant and telcagepant block key interactions of the CGRP C-terminal amide and F37 with the receptor pocket by hydrogen bonding with the CLR T122 main chain at the base of the pocket and packing of their piperidyl moieties against the Trp shelf and G71 (Figures 3C and 3D). Olcegepant also hydrogen bonds with CLR D94, thereby blocking the CGRP T30-CLR D94 interaction (Figure 3C). The position of RAMP1 relative to CLR in the peptide-bound versus drug-bound structures varies such that the drugs appear to favor RAMP1 α2 shifting closer to the small molecule binding sites (Figure 3E), presumably due to drug-RAMP1 interactions including packing against W74 (Figures 3C and 3D).\nSuperposition of the AM-bound and ligand-free CLR:RAMP2 complexes (Kusano et al., 2012) revealed minor CLR conformational differences involving the N-terminal region of α1 moving toward AM in the AM-bound state presumably due to AM-CLR T37 contacts (Figure 3F). CLR loops 3 and 4 do not move as in the CGRPmut-bound structure and there are no significant side-chain conformational differences at the peptide-binding site. The position of RAMP2 relative to CLR varies in the two structures (Figure 3F), but the ligand-free RAMP2 position is probably constrained by formation of the dimer of heterodimers in which the C-terminal end of RAMP2 α2 occupies the peptide-binding site of CLR from the opposing heterodimer (Figure 3G). Dimerization of the CLR:RAMP2 ECD heterodimer thus occludes the AM-binding site, which suggested that the RAMP2 L106R substitution (at the end of RAMP2 α2) was key to obtaining AM-bound crystals."}

{"project":"2_test","denotations":[{"id":"25982113-20826335-118216122","span":{"begin":160,"end":164},"obj":"20826335"},{"id":"25982113-20826335-118216122","span":{"begin":160,"end":164},"obj":"20826335"},{"id":"25982113-20826335-118216123","span":{"begin":900,"end":904},"obj":"20826335"},{"id":"25982113-20826335-118216123","span":{"begin":900,"end":904},"obj":"20826335"},{"id":"25982113-22102369-118216124","span":{"begin":1687,"end":1691},"obj":"22102369"},{"id":"25982113-22102369-118216124","span":{"begin":1687,"end":1691},"obj":"22102369"},{"id":"25982113-20826335-71076117","span":{"begin":160,"end":164},"obj":"20826335"},{"id":"25982113-20826335-71076117","span":{"begin":160,"end":164},"obj":"20826335"},{"id":"25982113-20826335-71076118","span":{"begin":900,"end":904},"obj":"20826335"},{"id":"25982113-20826335-71076118","span":{"begin":900,"end":904},"obj":"20826335"},{"id":"25982113-22102369-71076119","span":{"begin":1687,"end":1691},"obj":"22102369"},{"id":"25982113-22102369-71076119","span":{"begin":1687,"end":1691},"obj":"22102369"}],"text":"Comparisons to Ligand-free and Small Molecule Antagonist-Bound Structures\nSuperpositions of CGRPmut-bound and ligand-free CLR:RAMP1 complexes (ter Haar et al., 2010) revealed clamp-like movement of CLR loops 3 and 4 upon CGRPmut binding, presumably mediated by the CGRPmut T30-CLR D94 interaction and β-turn contacts with CLR loop 4 including the CGRPmut F35-CLR S117 interaction (Figures 3A and 3B). CLR R119 shifts to accommodate the peptide and RAMP1 F83 rotates away from CLR loop 4 (Figure 3B). The RAMP1 position relative to CLR varies in the structures (Figure 3A), but the positions of the α2-α3 loop and W84, which contacts CGRPmut F37, remain relatively similar (Figures 3A and 3B).\nThe CGRPmut-bound structure explains antagonism by the CGRP receptor-selective small molecule drugs olcegepant and telcagepant. Superposition of the CGRPmut-bound and drug-bound structures (ter Haar et al., 2010) indicated that olcegepant and telcagepant block key interactions of the CGRP C-terminal amide and F37 with the receptor pocket by hydrogen bonding with the CLR T122 main chain at the base of the pocket and packing of their piperidyl moieties against the Trp shelf and G71 (Figures 3C and 3D). Olcegepant also hydrogen bonds with CLR D94, thereby blocking the CGRP T30-CLR D94 interaction (Figure 3C). The position of RAMP1 relative to CLR in the peptide-bound versus drug-bound structures varies such that the drugs appear to favor RAMP1 α2 shifting closer to the small molecule binding sites (Figure 3E), presumably due to drug-RAMP1 interactions including packing against W74 (Figures 3C and 3D).\nSuperposition of the AM-bound and ligand-free CLR:RAMP2 complexes (Kusano et al., 2012) revealed minor CLR conformational differences involving the N-terminal region of α1 moving toward AM in the AM-bound state presumably due to AM-CLR T37 contacts (Figure 3F). CLR loops 3 and 4 do not move as in the CGRPmut-bound structure and there are no significant side-chain conformational differences at the peptide-binding site. The position of RAMP2 relative to CLR varies in the two structures (Figure 3F), but the ligand-free RAMP2 position is probably constrained by formation of the dimer of heterodimers in which the C-terminal end of RAMP2 α2 occupies the peptide-binding site of CLR from the opposing heterodimer (Figure 3G). Dimerization of the CLR:RAMP2 ECD heterodimer thus occludes the AM-binding site, which suggested that the RAMP2 L106R substitution (at the end of RAMP2 α2) was key to obtaining AM-bound crystals."}