Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2.
Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2.
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DOI：
10.1038/s41421-023-00610-7
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发表时间：
2023-11-28
期刊：
影响因子：
33.5
通讯作者：
Du, Yang
中科院分区：
文献类型：
--
作者：
Pan, Xin;Ye, Fang;Ning, Peiruo;Zhang, Zhiyi;Li, Xinyu;Zhang, Binghao;Wang, Qian;Chen, Geng;Gao, Wei;Qiu, Chen;Wu, Zhangsong;Li, Jiancheng;Zhu, Lizhe;Xia, Jiang;Gong, Kaizheng;Du, Yang
羟基羧酸受体2（HCAR 2）属于A类G蛋白偶联受体家族，在调节人体脂解和游离脂肪酸形成中起关键作用。它深入参与许多病理生理过程，并作为治疗心血管、肿瘤、自身免疫、神经退行性、炎症和代谢疾病的有吸引力的靶点。在这里，我们报告了四种有或没有激动剂的人HCAR 2-Gi 1复合物的冷冻电镜结构，包括药物烟酸（2.69 μ g）和阿昔莫司（3.23 μ g），高度亚型特异性激动剂MK-6892（3.25 μ g）和载脂蛋白形式（3.28 μ g）。结合分子动力学模拟和功能分析，我们揭示了HCAR 2对不同激动剂的识别机制，并总结了HCAR 2激动剂的一般药效团特征，这些药效团基于三个关键残基R1113.36，S17945.52和Y2847.43。值得注意的是，MK-6892-HCAR 2结构相对于其他激动剂结合的HCAR 2复合物显示出延伸的结合口袋。此外，还阐明了决定HCAR 2和HCAR 3之间配体选择性的关键残基。我们的研究结果为HCAR 2的配体识别，选择性，激活和G蛋白偶联机制提供了结构上的见解，这为设计新的HCAR 2靶向药物提供了启示，以获得更高的疗效，更高的选择性，更少或没有副作用。
Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2–Gi1 complexes with or without agonists, including the drugs niacin (2.69 Å) and acipimox (3.23 Å), the highly subtype-specific agonist MK-6892 (3.25 Å), and apo form (3.28 Å). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892–HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.
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影响因子：
64.8
作者：
Koehl A;Hu H;Maeda S;Zhang Y;Qu Q;Paggi JM;Latorraca NR;Hilger D;Dawson R;Matile H;Schertler GFX;Granier S;Weis WI;Dror RO;Manglik A;Skiniotis G;Kobilka BK
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Kobilka BK
影响因子：
64.8
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影响因子：
64.8
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Hua T;Vemuri K;Nikas SP;Laprairie RB;Wu Y;Qu L;Pu M;Korde A;Jiang S;Ho JH;Han GW;Ding K;Li X;Liu H;Hanson MA;Zhao S;Bohn LM;Makriyannis A;Stevens RC;Liu ZJ
通讯作者：
Liu ZJ
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
影响因子：
64.8
作者：
Kang Y;Kuybeda O;de Waal PW;Mukherjee S;Van Eps N;Dutka P;Zhou XE;Bartesaghi A;Erramilli S;Morizumi T;Gu X;Yin Y;Liu P;Jiang Y;Meng X;Zhao G;Melcher K;Ernst OP;Kossiakoff AA;Subramaniam S;Xu HE
通讯作者：
Xu HE