Assistant Professor Fang Ye and her collaborators revealed the molecular mechanism of HCAR3 ligand recognition and downstream of G protein recruitment in Cell Reports

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G protein coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors superfamily in the human genome and are important and popular targets in drug development. The hydroxycarboxylic acid receptors (HCAR) family belong to Class A GPCRs, including three members: HCAR1, HCAR2, and HCAR3. They are important metabolic sensors in humans. HCAR3 is expressed in multiple cell types, including adipocytes, immune cells, macrophages, and intestinal epithelial cells. In addition, HCAR3 has been shown to be involved in sepsis and coronary heart disease and was identified as a potential target in colorectal and breast cancer.

Recently, Dr. Ye Fang from the Guangxi Key Laboratory of Special Biomedicine/School of Medicine of Guangxi University, together with teams from Yangzhou University and the Chinese University of Hong Kong (Shenzhen), published a research paper entitled "Structural basis for ligand recognition of the human hydroxycarboxylic acid receptor HCAR3" in the journal Cell Reports. In this study, single-particle cryoelectron microscopy (cryo-EM) was used to determine the structures of human HCAR3 in complex with the heterotrimeric Gi1 protein: HCAR3 bound to the endogenous ligand 3HO, the drug niacin, the highly subtype-specific agonist compound 5c, and in the absence of a ligand (apo state). In combination with computational modeling, molecular dynamics (MD), and mutagenesis results, these structures revealed the ligand recognition and selectivity, receptor activation, and Gi protein coupling of HCAR3. More importantly, the structural information provided multiple templates for the rational design of therapeutics targeting HCAR3.

The co-first authors of the paper are Dr. Ye Fang from the School of Medicine of Guangxi University, Dr. Pan Xin of Yangzhou University, Dr. Xiang Xufu from Huazhong University of Science and Technology, and Zhang Zhiyi and Li Xinyu from the Chinese University of Hong Kong (Shenzhen). The co-corresponding authors are Professor Du Yang, Assistant Professor Chen Geng, Professor Zhu Lizhe from the Chinese University of Hong Kong (Shenzhen), and Professor Qian Chungeng from Huazhong University of Science and Technology. The Kobilka Cryo-EM Center of the Chinese University of Hong Kong (Shenzhen) provided the platform for this study. This research was supported by the Guangxi University Talent Research Fund, the National Natural Science Foundation of China and other projects.