8jii | pdb_00008jii

Cryo-EM structure of compound 9n and niacin bound ketone body receptor HCAR2-Gi signaling complex

spinqualitylabelsall models 8jii, resolution 3.17Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8jii is a 5 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.17Å Ligands: CLR, IX8, NIO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Publication Abstract from PubMed Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body beta-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating G(i/o) protein or beta-arrestin effectors. Here, we characterize compound 9n as a G(i)-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-G(i) pathway. Furthermore, four structures of HCAR2-G(i) 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. Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.,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 Mol Cell. 2023 Aug 11:S1097-2765(23)00605-6. doi: 10.1016/j.molcel.2023.07.030. PMID:37597514 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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