GPCR structure and function beyond class A

Orateur : Vadim CHEREZOV (The Scripps Research Institute, La Jolla, USA)

G protein-coupled receptors (GPCRs) comprise the largest protein superfamily in the human proteome with about 800 members. Based on sequence homology these receptors are grouped in 5 families : Rhodopsin family (class A), Secretin family (class B), Glutamate family (class C), Adhesion family and Frizzled/TAS2 family. GPCR-mediated signaling pathways are implicated in numerous human diseases, making these receptors to serve as attractive targets for drug development. During the last few years, GPCR crystallography has experienced exponential growth. By the end of 2012, structures of 16 different GPCRs (all from class A) have been determined, giving unprecedented details on diversity of ligand-receptor interactions and the mechanism of signal transduction. Here I will present structures of two non-class A GPCRs : glucagon receptor (GLR, class B) and smoothened receptor (SMO, Frizzled family). Both receptors retain the common 7TM fold, while showing a number of substantial deviations from class A structures and unique structural motifs, likely inherent to members of corresponding families. These new data expand our understanding of structure and function relationship for GPCR superfamily beyond class A and provide new clues on GPCR evolution.

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