Structural basis for ligand recognition of the human hydroxycarboxylic acid receptor HCAR3

• Published in: Cell reports (Cambridge) 2024-11, Vol.43 (11), p.114895, Article 114895
• Main Authors: Ye, Fang, Pan, Xin, Zhang, Zhiyi, Xiang, Xufu, Li, Xinyu, Zhang, Binghao, Ning, Peiruo, Liu, Aijun, Wang, Qinggong, Gong, Kaizheng, Li, Jiancheng, Zhu, Lizhe, Qian, Chungen, Chen, Geng, Du, Yang
• Format: Article
• Language: English
• Subjects: CP: Molecular biology; Cryoelectron Microscopy; HEK293 Cells; Humans; Ligands; Niacin - analogs & derivatives; Niacin - chemistry; Niacin - metabolism; Protein Binding; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Receptors, Nicotinic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114895

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. [Display omitted] •Four cryo-EM structures of human HCAR3-Gi1 complex with or without agonists•Diverse binding modes of 3HO-, niacin-, and compound 5c-HCAR3 structures•The residue Y2847.43 is a conserved site for the binding of HCAR3 agonists•The interaction interface between HCAR3 and Gi1 Ye et al. report four cryo-EM structures of Gi-coupled HCAR3 with or without agonists, including 3HO, niacin, compound 5c, and the apo form. The work illustrates the mechanisms of ligand recognition and selectivity, as well as the interaction interface between HCAR3 and Gi1.