6PFO

Crystal structure of N-glycosylated human calcitonin receptor extracellular domain in complex with salmon calcitonin (16-32)

6PFO の概要

• エントリーDOI: 10.2210/pdb6pfo/pdb
• 関連するBIRD辞書のPRD_ID: PRD_900001
• 分子名称: Maltodextrin-binding protein,Calcitonin receptor, Calcitonin, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: class b gpcr, glcnac, signaling protein
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 114056.06

構造登録者

Lee, S.,Pioszak, A.A. (登録日: 2019-06-21, 公開日: 2020-02-12, 最終更新日: 2020-07-29)

主引用文献

Lee, S.M.,Jeong, Y.,Simms, J.,Warner, M.L.,Poyner, D.R.,Chung, K.Y.,Pioszak, A.A.
Calcitonin Receptor N-Glycosylation Enhances Peptide Hormone Affinity by Controlling Receptor Dynamics.
J.Mol.Biol., 432:1996-2014, 2020

PubMed Abstract: 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 Å 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 β-sheet adjacent to the N130 GlcNAc and the N-terminal α-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.

PubMed: 32035902
DOI: 10.1016/j.jmb.2020.01.028

実験手法

X-RAY DIFFRACTION (1.78 Å)