Hot Topics: Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor

In this multi-author, multi-centre publication [1] lead by Denise Wootten and Patrick Sexton from the Monash Institute of Pharmacological Sciences, there is reported a 3.3 Angstrom structure of one of the more unusual G protein-coupled receptors. The CGRP receptor is a target for the recently FDA-approved monoclonal antibody erenumab targetting migraine. The receptor is unusual because of its modulation by a trio of accessory proteins exemplified here by RAMP1, which influence both the pharmacological and signalling profiles of the GPCR. Recent structural approaches to studies of GPCR have moved into investigations where a G protein is included. The Liang paper has a Gs heterotrimer attached, and, in addition, has the natural ligand, CGRP bound to the receptor. The report on this six molecule complex thus allows a major advance into the interaction between a GPCR, its endogenous agonist, the requisite G protein AND a modulatory protein.

Comments by Steve Alexander (@mqzspa)

(1) Liang YL et al. (2018). Cryo-EM structure of the active, G_s-protein complexed, human CGRP receptor. Nature, doi: 10.1038/s41586-018-0535-y. [Epub ahead of print]. [PMID: 30175587]