8j6j

Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound with GSK256073

spinqualitylabelsall models 8j6j, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8j6j is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.8Å Ligands: OKL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Niacin, 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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