8AX5

Crystal structure of a CGRP receptor ectodomain heterodimer bound to macrocyclic inhibitor HTL0029881

8AX5 の概要

• エントリーDOI: 10.2210/pdb8ax5/pdb
• 関連するBIRD辞書のPRD_ID: PRD_900001
• 分子名称: Maltose/maltodextrin-binding periplasmic protein,Receptor activity-modifying protein 1,Calcitonin gene-related peptide type 1 receptor, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, (1~{R},10~{R},20~{E})-12-methyl-10-[(7-methyl-2~{H}-indazol-5-yl)methyl]-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.1^{1,4}.1^{3,7}.0^{25,28}]hentriaconta-3,5,7(30),20,22,24,28-heptaene-8,11,27-trione, ... (5 entities in total)
• 機能のキーワード: cgrp, cgrpr, ectodomain, ramp, macrocycle, macrocyclic, membrane protein
• 由来する生物種: Escherichia coli K-12; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 67445.71

構造登録者

Southall, S.M.,Watson, S.P. (登録日: 2022-08-30, 公開日: 2022-12-07, 最終更新日: 2024-11-20)

主引用文献

Southall, S.M.,Banerjee, J.,Brown, J.,Butkovic, K.,Cansfield, A.D.,Cansfield, J.E.,Congreve, M.S.,Cseke, G.,Deflorian, F.,Hunjadi, M.P.,Hutinec, A.,Inturi, T.K.,Rupcic, R.,Saxty, G.,Watson, S.P.
Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode.
Acs Med.Chem.Lett., 13:1776-1782, 2022

PubMed Abstract: The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 () and HTL0029882 (), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that binds to the CGRP receptor in a precedented manner but that binds in an unprecedented, unexpected, and radically different manner. The observation of this phenomenon is noteworthy and may open novel avenues for CGRP receptor antagonist design.

PubMed: 36385934
DOI: 10.1021/acsmedchemlett.2c00400

実験手法

X-RAY DIFFRACTION (2.75 Å)