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.
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.
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