Structural basis of G_s and G_i recognition by the human glucagon receptor.

Abstract

Class B G protein-coupled receptors, an important class of therapeutic targets, signal mainly through the G_s class of heterotrimeric G proteins, although they do display some promiscuity in G protein binding. Using cryo-electron microscopy, we determined the structures of the human glucagon receptor (GCGR) bound to glucagon and distinct classes of heterotrimeric G proteins, G_s or G_i1 These two structures adopt a similar open binding cavity to accommodate G_s and G_i1 The G_s binding selectivity of GCGR is explained by a larger interaction interface, but there are specific interactions that affect G_i more than G_s binding. Conformational differences in the receptor intracellular loops were found to be key selectivity determinants. These distinctions in transducer engagement were supported by mutagenesis and functional studies.