8j6i
Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound MK-6892
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 PubMedNiacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled receptor (GPCR). Yet, its use is hindered by side effects like skin flushing. To address this, specific HCAR2 agonists, like MK-6892 and GSK256073, with fewer adverse effects have been created. However, the activation mechanism of HCAR2 by niacin and these new agonists is not well understood. Here, we present three cryoelectron microscopy structures of Gi-coupled HCAR2 bound to niacin, MK-6892, and GSK256073. Our findings show that different ligands induce varying binding pockets in HCAR2, influenced by aromatic amino acid clusters (W91(ECL1), H161(4.59), W188(5.38), H189(5.39), and F193(5.43)) from receptors ECL1, TM4, and TM5. Additionally, conserved residues R111(3.36) and Y284(7.43), unique to the HCA receptor family, likely initiate activation signal propagation in HCAR2. This study provides insights into ligand recognition, receptor activation, and G protein coupling mediated by HCAR2, laying the groundwork for developing HCAR2-targeted drugs. Molecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2.,Zhu S, Yuan Q, Li X, He X, Shen S, Wang D, Li J, Cheng X, Duan X, Xu HE, Duan J Cell Rep. 2023 Nov 28;42(11):113406. doi: 10.1016/j.celrep.2023.113406. Epub 2023 , Nov 11. PMID:37952153[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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