Structural insights into differences in G protein activation by family A and family B GPCRs

Abstract

Revealing family differences In response to low blood glucose concentrations, both the glucagon receptor (GCGR)—a family B G protein–coupled receptor (GPCR)—and the β 2 adrenergic receptor (β 2 AR)—a family A GPCR—are activated and act through the cyclic adenosine monophosphate signaling pathway to increase glucose production. The kinetics of the response is different for the two receptors. Based on structural and spectroscopic data, Hilger et al. show that the conformation of transmembrane helix 6 in the activated state is a key differentiator (see the Perspective by Lebon). In β 2 AR, the helix moves toward its active conformation when an agonist binds, but in GCGR, both agonist and G protein binding are required. This likely explains why activation of its partner G protein is slower for GCGR than for β 2 AR. Science , this issue p. eaba3373 ; see also p. 507