Structural insights into endogenous ligand selectivity and activation mechanisms of FFAR1 and FFAR2
Yudun Ke,
Yimiao Huang,
Cuiying Yi,
Limin Ma,
Xiaojing Chu,
Beili Wu,
Qiang Zhao,
Shuo Han
Affiliations
Yudun Ke
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China
Yimiao Huang
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China
Cuiying Yi
State Key Laboratory of Drug Research, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Limin Ma
State Key Laboratory of Drug Research, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Xiaojing Chu
State Key Laboratory of Drug Research, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Beili Wu
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; State Key Laboratory of Drug Research, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310020, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China; Corresponding author
Qiang Zhao
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; State Key Laboratory of Drug Research, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; Corresponding author
Shuo Han
State Key Laboratory of Drug Research, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310020, China; Corresponding author
Summary: Free fatty acid receptors (FFARs) play critical roles in metabolic regulation and are potential therapeutic targets for metabolic and inflammatory diseases. A comprehensive understanding of the activation mechanisms and endogenous ligand selectivity of FFARs is essential for drug discovery. Here, we report two cryoelectron microscopy structures of the human FFAR1 bound to the endogenous ligand docosahexaenoic acid (DHA) and Gi1 protein as well as FFAR2 in complex with butyrate and Gi1 at 3.2 Å and 3.3 Å resolution, respectively. These structures highlight that distinct locations and sizes of the orthosteric ligand binding pockets are crucial determinants of the endogenous ligand selectivity of this receptor subfamily. Additionally, computational analysis reveals a potential allosteric ligand binding pocket in FFAR2. Furthermore, we observe that the upward movement of helix V upon endogenous ligand binding is responsible for receptor activation. These insights will significantly aid in the development of drugs targeting this receptor family.
