8k5d
Cryo-EM structure of GSK256073 bound human hydroxy-carboxylic acid receptor 2 (Local refinement)
Structural highlights
FunctionHCAR2_HUMAN Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5-methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox >> nicotinuric acid = nicotinamide.[1] Publication Abstract from PubMedHydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce G(i/o) signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with lipolytic and atherogenic activity, and neuroinflammation. Although many reports have elucidated the function of HCAR2 and its potential as a therapeutic target for treating not only dyslipidemia but also neuroimmune disorders such as multiple sclerosis and Parkinson's disease, the structural basis of ligand recognition and ligand-induced G(i)-coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2-G(i) signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. All three agonists are held in a deep pocket lined by residues that are not conserved in HCAR1 and HCAR3. A distinct hairpin loop at the HCAR2 N-terminus and extra-cellular loop 2 (ECL2) completely enclose the ligand. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation. Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2.,Park JH, Kawakami K, Ishimoto N, Ikuta T, Ohki M, Ekimoto T, Ikeguchi M, Lee DS, Lee YH, Tame JRH, Inoue A, Park SY Nat Commun. 2023 Nov 6;14(1):7150. doi: 10.1038/s41467-023-42764-8. PMID:37932263[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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