EMD-36737

Single-particle
2.6 Å
EMD-36737 Deposition: 04/07/2023
Map released: 04/10/2023
Last modified: 04/10/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-36737

Cryo-EM map of MK-6892-bound HCAR2 in complex with Gi protein

EMD-36737

Single-particle
2.6 Å
EMD-36737 Deposition: 04/07/2023
Map released: 04/10/2023
Last modified: 04/10/2023
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Mus musculus
Sample: MK6892-bound HCAR2 in complex with Gi heterotrimer

Deposition Authors: Zhao C , Tian XW, Cheng L, Liu Y, Yan W, Shao ZH
Orthosteric ligand selectivity and allosteric probe dependence at Hydroxycarboxylic acid receptor HCAR2.
Cheng L, Sun S, Wang H, Zhao C , Tian X, Liu Y, Fu P , Shao Z , Chai R , Yan W
(2023) Signal Transduct Target Ther , 8 , 364 - 364
PUBMED: 37743365
DOI: doi:10.1038/s41392-023-01625-y
ISSN: 2059-3635
Abstract:
Hydroxycarboxylic acid receptor 2 (HCAR2), a member of Class A G-protein-coupled receptor (GPCR) family, plays a pivotal role in anti-lipolytic and anti-inflammatory effects, establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases. However, the mechanism underlying the signaling of HCAR2 induced by various types of ligands remains elusive. In this study, we elucidate the cryo-electron microscopy (cryo-EM) structure of Gi-coupled HCAR2 in complex with a selective agonist, MK-6892, resolved to a resolution of 2.60 Å. Our structural analysis reveals that MK-6892 occupies not only the orthosteric binding pocket (OBP) but also an extended binding pocket (EBP) within HCAR2. Pharmacological assays conducted in this study demonstrate that the OBP is a critical determinant for ligand selectivity among the HCARs subfamily. Moreover, we investigate the pharmacological properties of the allosteric modulator compound 9n, revealing its probe-dependent behavior on HCAR2 in response to varying orthosteric agonists. Collectively, our findings provide invaluable structural insights that contribute to a deeper understanding of the regulatory mechanisms governing HCAR2 signaling transduction mediated by both orthosteric and allosteric ligands.