Structural basis for ligand recognition of the human hydroxycarboxylic acid receptor HCAR3
Fang Ye,
Xin Pan,
Zhiyi Zhang,
Xufu Xiang,
Xinyu Li,
Binghao Zhang,
Peiruo Ning,
Aijun Liu,
Qinggong Wang,
Kaizheng Gong,
Jiancheng Li,
Lizhe Zhu,
Chungen Qian,
Geng Chen,
Yang Du
Affiliations
Fang Ye
Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China; Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China
Xin Pan
Department of Cardiology, Central Laboratory, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, Jiangsu, China
Zhiyi Zhang
Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China
Xufu Xiang
The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics - Hubei Bioinformatics and Molecular Imaging Key Laboratory, Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
Xinyu Li
Warshel Institute for Computational Biology, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China
Binghao Zhang
Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China
Peiruo Ning
Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China
Aijun Liu
Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China
Qinggong Wang
Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China
Kaizheng Gong
Department of Cardiology, Central Laboratory, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, Jiangsu, China
Jiancheng Li
Instrumental Analysis Center, Shenzhen University, Shenzhen 518060, Guangdong, China
Lizhe Zhu
Warshel Institute for Computational Biology, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China; Corresponding author
Chungen Qian
The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics - Hubei Bioinformatics and Molecular Imaging Key Laboratory, Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; Corresponding author
Geng Chen
Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China; Corresponding author
Yang Du
Kobilka Institute of Innovative Drug Discovery, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, Guangdong, China; Corresponding author
Summary: Hydroxycarboxylic acid receptor 3 (HCAR3), a class A G-protein-coupled receptor, is an important cellular energy metabolism sensor with a key role in the regulation of lipolysis in humans. HCAR3 is deeply involved in many physiological processes and serves as a valuable target for the treatment of metabolic diseases, tumors, and immune diseases. Here, we report four cryoelectron microscopy (cryo-EM) structures of human HCAR3-Gi1 complexes with or without agonists: the endogenous ligand 3-hydroxyoctanoic acid, the drug niacin, the highly subtype-specific agonist compound 5c (4-(n-propyl)amino-3-nitrobenzoic acid), and the apo form. Together with mutagenesis and functional analyses, we revealed the recognition mechanisms of HCAR3 for different agonists. In addition, the key residues that determine the ligand selectivity between HCAR2 and HCAR3 were also illuminated. Overall, these findings provide a structural basis for the ligand recognition, activation, and selectivity and G-protein coupling mechanisms of HCAR3, which contribute to the design of HCAR3-targeting drugs with high efficacy and selectivity.
