Cryo-EM structures of orphan GPR21 signaling complexes

In this work, the authors report Cryo-EM structures of the signaling complexes of human GPR21, an orphan GPCR and a potential metabolic disease target, and reveal unique receptor activation conformation when bound to downstream signaling proteins in the absence of any ligand. GPR21 is a class-A orphan G protein-coupled receptor (GPCR) and a potential therapeutic target for type 2 diabetes and other metabolic disorders. This receptor shows high basal activity in coupling to multiple G proteins in the absence of any known endogenous agonist or synthetic ligand. Here, we present the structures of ligand-free human GPR21 bound to heterotrimeric miniGs and miniG15 proteins, respectively. We identified an agonist-like motif in extracellular loop 2 (ECL2) that occupies the orthosteric pocket and promotes receptor activation. A side pocket that may be employed as a new ligand binding site was also uncovered. Remarkably, G protein binding is accommodated by a flexible cytoplasmic portion of transmembrane helix 6 (TM6) which adopts little or undetectable outward movement. These findings will enable the design of modulators for GPR21 for understanding its signal transduction and exploring opportunity for deorphanization.

Automated summary

In this study, the Cryo-EM structures of human GPR21 signaling complexes were determined, revealing a unique receptor activation conformation in the absence of any ligand when bound to downstream signaling proteins. GPR21 is an orphan GPCR and a potential therapeutic target for metabolic disorders. The structures of ligand-free GPR21 bound to miniGs and miniG15 proteins were presented, showing an agonist-like motif in ECL2 and a potential new ligand binding site. The flexible cytoplasmic portion of TM6 accommodates G protein binding without significant outward movement. These findings provide insights for modulator design and understanding signal transduction of GPR21.