8HJ1

GPR21(wt) and Gs complex

Summary for 8HJ1

• Entry DOI: 10.2210/pdb8hj1/pdb
• EMDB information: 33483
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (5 entities in total)
• Functional Keywords: gpcr, orphan receptor, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 133550.97

Authors

Chen, B.,Lin, X.,Xu, F. (deposition date: 2022-11-22, release date: 2023-12-27)

Primary citation

Lin, X.,Chen, B.,Wu, Y.,Han, Y.,Qi, A.,Wang, J.,Yang, Z.,Wei, X.,Zhao, T.,Wu, L.,Xie, X.,Sun, J.,Zheng, J.,Zhao, S.,Xu, F.
Cryo-EM structures of orphan GPR21 signaling complexes.
Nat Commun, 14:216-216, 2023

PubMed Abstract: 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.

PubMed: 36639690
DOI: 10.1038/s41467-023-35882-w

Experimental method

ELECTRON MICROSCOPY (3.27 Å)