8JIL

Cryo-EM structure of niacin bound ketone body receptor HCAR2-Gi signaling complex

Summary for 8JIL

• Entry DOI: 10.2210/pdb8jil/pdb
• EMDB information: 36317 36494 36495 36507
• Descriptor: 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, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (8 entities in total)
• Functional Keywords: complex, agonist, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 162597.61

Authors

Zhao, C.,Tian, X.W.,Liu, Y.,Cheng, L.,Yan, W.,Shao, Z.H. (deposition date: 2023-05-26, release date: 2023-09-06, Last modification date: 2024-10-23)

Primary citation

Zhao, C.,Wang, H.,Liu, Y.,Cheng, L.,Wang, B.,Tian, X.,Fu, H.,Wu, C.,Li, Z.,Shen, C.,Yu, J.,Yang, S.,Hu, H.,Fu, P.,Ma, L.,Wang, C.,Yan, W.,Shao, Z.
Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.
Mol.Cell, 83:3171-, 2023

PubMed Abstract: Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating G protein or β-arrestin effectors. Here, we characterize compound 9n as a G-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-G pathway. Furthermore, four structures of HCAR2-G complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs.

PubMed: 37597514
DOI: 10.1016/j.molcel.2023.07.030

Experimental method

ELECTRON MICROSCOPY (3.5 Å)