Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism.
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.
ter Haar
Ernst
E
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, USA.
Koth
Christopher M
CM
Abdul-Manan
Norzehan
N
Swenson
Lora
L
Coll
Joyce T
JT
Lippke
Judith A
JA
Lepre
Christopher A
CA
Garcia-Guzman
Miguel
M
Moore
Jonathan M
JM
D001381:Azepines / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D015740:Calcitonin Gene-Related Peptide / Q000737:chemistry / Q000378:metabolism; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D058286:Calcitonin Receptor-Like Protein / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000737:chemistry* / Q000378:metabolism
D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D058286:Calcitonin Receptor-Like Protein; D007093:Imidazoles; D010879:Piperazines; D011799:Quinazolines; D018015:Receptors, Calcitonin Gene-Related Peptide; C525458:telcagepant; D015740:Calcitonin Gene-Related Peptide; C406305:olcegepant