3N7P

Crystal structure of the ectodomain complex of the CGRP receptor, a Class-B GPCR, reveals the site of drug antagonism

3N7P の概要

• エントリーDOI: 10.2210/pdb3n7p/pdb
• 関連するPDBエントリー: 3N7R 3N7S
• 分子名称: Calcitonin gene-related peptide type 1 receptor, Receptor activity-modifying protein 1, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: gpcr, class b gpcr, antagonist, olcegepant, telcagepant, migraine, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cell membrane; Multi-pass membrane protein: Q16602; Membrane; Single-pass type I membrane protein: O60894
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 99836.53

構造登録者

Ter Haar, E. (登録日: 2010-05-27, 公開日: 2010-09-15, 最終更新日: 2024-11-06)

主引用文献

Ter Haar, E.,Koth, C.M.,Abdul-Manan, N.,Swenson, L.,Coll, J.T.,Lippke, J.A.,Lepre, C.A.,Garcia-Guzman, M.,Moore, J.M.
Crystal Structure of the Ectodomain Complex of the CGRP Receptor, a Class-B GPCR, Reveals the Site of Drug Antagonism.
Structure, 18:1083-1093, 2010

PubMed Abstract: Dysregulation of the calcitonin gene-related peptide (CGRP), a potent vasodilator, is directly implicated in the pathogenesis of migraine. CGRP binds to and signals through the CGRP receptor (CGRP-R), a heterodimer containing the calcitonin receptor-like receptor (CLR), a class B GPCR, and RAMP1, a receptor activity-modifying protein. We have solved the crystal structure of the CLR/RAMP1 N-terminal ectodomain heterodimer, revealing how RAMPs bind to and potentially modulate the activities of the CLR GPCR subfamily. We also report the structures of CLR/RAMP1 in complex with the clinical receptor antagonists olcegepant (BIBN4096BS) and telcagepant (MK0974). Both drugs act by blocking access to the peptide-binding cleft at the interface of CLR and RAMP1. These structures illustrate, for the first time, how small molecules bind to and modulate the activity of a class B GPCR, and highlight the challenges of designing potent receptor antagonists for the treatment of migraine and other class B GPCR-related diseases.

PubMed: 20826335
DOI: 10.1016/j.str.2010.05.014

実験手法

X-RAY DIFFRACTION (2.8 Å)