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.


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.

MeSH terms

  • Azepines / chemistry*
  • Azepines / pharmacology
  • Binding Sites
  • Calcitonin Gene-Related Peptide / chemistry
  • Calcitonin Gene-Related Peptide / metabolism
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Calcitonin Receptor-Like Protein / chemistry
  • Calcitonin Receptor-Like Protein / metabolism
  • Crystallography, X-Ray
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Protein Structure, Tertiary
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology
  • Receptors, Calcitonin Gene-Related Peptide / chemistry*
  • Receptors, Calcitonin Gene-Related Peptide / metabolism


  • Azepines
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Calcitonin Receptor-Like Protein
  • Imidazoles
  • Piperazines
  • Quinazolines
  • Receptors, Calcitonin Gene-Related Peptide
  • telcagepant
  • Calcitonin Gene-Related Peptide
  • olcegepant

Associated data

  • PDB/3N7P
  • PDB/3N7R
  • PDB/3N7S