School of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Department of Pharmacology, Guilin Medical University, Guilin 541004, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Cell Rep. 2023 Nov 28;42(11):113406. doi: 10.1016/j.celrep.2023.113406. Epub 2023 Nov 11.
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.
烟酸是一种古老的降脂药物，通过羟基羧酸受体 2（HCAR2）发挥作用，HCAR2 是一种 G 蛋白偶联受体（GPCR）。然而，其使用受到皮肤潮红等副作用的限制。为了解决这个问题，已经开发出了具有较少副作用的特定 HCAR2 激动剂，如 MK-6892 和 GSK256073。然而，烟酸和这些新激动剂激活 HCAR2 的机制尚不清楚。在这里，我们展示了三种与 Gi 偶联的 HCAR2 结合烟酸、MK-6892 和 GSK256073 的冷冻电子显微镜结构。我们的研究结果表明，不同的配体在 HCAR2 中诱导不同的结合口袋，这受到来自受体 ECL1、TM4 和 TM5 的芳香族氨基酸簇（W91、H161、W188、H189 和 F193）的影响。此外，保守残基 R111 和 Y284 是 HCA 受体家族所特有的，可能在 HCAR2 中启动激活信号的传播。这项研究为开发 HCAR2 靶向药物提供了关于配体识别、受体激活和 G 蛋白偶联的见解。
