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-Structure paper
タイトル | Molecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2. |
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ジャーナル・号・ページ | Cell Rep, Vol. 42, Issue 11, Page 113406, Year 2023 |
掲載日 | 2023年11月28日 |
著者 | Shengnan Zhu / Qingning Yuan / Xinzhu Li / Xinheng He / Shiyi Shen / Dongxue Wang / Junrui Li / Xi Cheng / Xiaoqun Duan / H Eric Xu / Jia Duan / |
PubMed 要旨 | 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. ...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, H161, W188, H189, and F193) from receptors ECL1, TM4, and TM5. Additionally, conserved residues R111 and Y284, 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. |
リンク | Cell Rep / PubMed:37952153 |
手法 | EM (単粒子) |
解像度 | 2.8 - 3.05 Å |
構造データ | EMDB-36005, PDB-8j6i: EMDB-36006, PDB-8j6j: EMDB-36007, PDB-8j6l: |
化合物 | ChemComp-FI7: ChemComp-OKL: ChemComp-NIO: |
由来 |
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キーワード | MEMBRANE PROTEIN/IMMUNE SYSTEM (生体膜) / hydroxycarboxylic acid receptor 2 / GPCR (Gタンパク質共役受容体) / niacin (ニコチン酸) / MK-6892 / GSK256073 / MEMBRANE PROTEIN (膜タンパク質) / MEMBRANE PROTEIN-IMMUNE SYSTEM complex (生体膜) |