烟酸,一种古老的降脂药,通过羟基羧酸受体2(HCAR2),G蛋白偶联受体(GPCR)。然而,它的使用受到皮肤潮红等副作用的阻碍。为了解决这个问题,特异性HCAR2激动剂,如MK-6892和GSK256073,产生的不良反应较少。然而,烟酸和这些新的激动剂对HCAR2的激活机制尚不清楚.这里,我们介绍了与烟酸结合的Gi偶联HCAR2的三种冷冻电子显微镜结构,MK-6892和GSK256073。我们的发现表明,不同的配体在HCAR2中诱导不同的结合口袋,受受体ECL1,TM4和TM5的芳香族氨基酸簇(W91ECL1,H1614.59,W1885.38,H1895.39和F1935.43)的影响。此外,HCA受体家族特有的保守残基R1113.36和Y2847.43,可能在HCAR2中启动激活信号传播。这项研究提供了对配体识别的见解,受体激活,和HCAR2介导的G蛋白偶联,为开发HCAR2靶向药物奠定基础。
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 (W91ECL1, H1614.59, W1885.38, H1895.39, and F1935.43) from receptors ECL1, TM4, and TM5. Additionally, conserved residues R1113.36 and Y2847.43, 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.