6pgq

Crystal structure of N-glycosylated human calcitonin receptor extracellular domain in complex with salmon calcitonin (22-32)

spinqualitylabelsall models 6pgq, resolution 2.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6pgq is a 2 chain structure with sequence from "bacillus_coli"_migula_1895 "bacillus coli" migula 1895. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, MAL, NAG NonStd Res: NH2 Related: 6pfo Gene: CALCR ("Bacillus coli" Migula 1895) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The class B G protein-coupled receptor (GPCR) calcitonin receptor (CTR) is a drug target for osteoporosis and diabetes. N-glycosylation of asparagine 130 in its extracellular domain (ECD) enhances calcitonin hormone affinity with the proximal GlcNAc residue mediating this effect through an unknown mechanism. Here, we present two crystal structures of salmon calcitonin-bound, GlcNAc-bearing CTR ECD at 1.78 and 2.85 A resolutions and analyze the mechanism of the glycan effect. The N130 GlcNAc does not contact the hormone. Surprisingly, the structures are nearly identical to a structure of hormone-bound, N-glycan-free ECD, which suggested that the GlcNAc might affect CTR dynamics not observed in the static crystallographic snapshots. Hydrogen-deuterium exchange mass spectrometry and molecular dynamics simulations revealed that glycosylation stabilized a beta-sheet adjacent to the N130 GlcNAc and the N-terminal alpha-helix near the peptide-binding site, while increasing flexibility of the peptide-binding site turret loop. These changes due to N-glycosylation increased the ligand on-rate and decreased its off rate. The glycan effect extended to RAMP-CTR amylin receptor complexes and was also conserved in the related CGRP receptor. These results reveal that N-glycosylation can modulate GPCR function by altering receptor dynamics. Calcitonin receptor N-glycosylation enhances peptide hormone affinity by controlling receptor dynamics.,Lee SM, Jeong Y, Simms J, Warner ML, Poyner DR, Chung KY, Pioszak AA J Mol Biol. 2020 Feb 6. pii: S0022-2836(20)30092-9. doi:, 10.1016/j.jmb.2020.01.028. PMID:32035902 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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