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

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ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT, Lippke JA, Lepre CA, Garcia-Guzman M, Moore JM

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

Structure. 2010 Sep 8;18(9):1083-93. doi: 10.1016/j.str.2010.05.014.

PubMed ID
20826335 [ View in 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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Receptor activity-modifying protein 1O60894Details
Calcitonin gene-related peptide type 1 receptorQ16602Details