8HMV

Structure of GPR21-Gs complex

Summary for 8HMV

• Entry DOI: 10.2210/pdb8hmv/pdb
• EMDB information: 34903
• Descriptor: Probable G-protein coupled receptor 21, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (5 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 135102.44

Authors

Wong, T.S.,Gao, W. (deposition date: 2022-12-05, release date: 2023-03-01, Last modification date: 2024-11-13)

Primary citation

Wong, T.S.,Gao, W.,Chen, G.,Qiu, C.,He, G.,Ye, F.,Wu, Z.,Zeng, Z.,Du, Y.
Cryo-EM structure of orphan G protein-coupled receptor GPR21.
MedComm (2020), 4:e205-e205, 2023

PubMed Abstract: GPR21 belongs to class A orphan G protein-coupled receptor (GPCR). The endogenous ligands for human GPR21 remain unidentified. GPR21 expression is associated with developing type 2 diabetes (T2DM), a multifactorial metabolic disease caused by pancreatic β-cell dysfunction, decreasing insulin production, insulin resistance, and obesity. Animal studies suggested that GPR21 is a potential therapeutic target for T2DM treatment. The underlying mechanisms leading to GPR21 self-activation remain unknown. In our co-expression analysis, we noted that GPR21 could also form a stable complex with an unreported Gα protein subtype, Gαs. To gain further insights into the structural mechanisms of GPR21 activation, we employed cryo-electron microscopy (cryo-EM) and single-particle analysis to resolve the high-resolution structure of GPR21-Gαs complexes. The clear electron density map of the GPR21-Gαs provided direct evidence that GPR21 could couple to Gαs protein at physiological conditions. Thus, GPR21 might mediate previously unexplored pathways in normal or pathological conditions, which warrants further investigation. Structure-guided mutagenesis and biochemical analysis revealed that extracellular loop 2 (ECL2) of GPR21 is essential for the receptor transducing intracellular signal via cAMP. Together, the new structure data reveal a novel signaling cascade of human GPR21 mediated by ECL2 and provide fundamental information for future structure-based drug development.

PubMed: 36721851
DOI: 10.1002/mco2.205

Experimental method

ELECTRON MICROSCOPY (2.91 Å)