机构：[1]Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, SichuanUniversity, Chengdu 610041, Sichuan, China四川大学华西医院[2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China[3]Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science andTechnology of China, Chengdu 610000, Sichuan, China四川省人民医院[4]Department of Rheumatology and Immunology, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, WestChina Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, Sichuan, China[5]Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, Shandong, China
Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body b-hydroxybutyrate and
exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates
distinct pathophysiological events by activating Gi/o protein or b-arrestin effectors. Here, we characterize
compound 9n as a Gi
-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy
in RAW264.7 macrophages via a specific HCAR2-Gi pathway. Furthermore, four structures of HCAR2-Gi
complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together
with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined
with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on
the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance
anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand
the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM
with orthosteric drugs.
基金：
Cryo-EM data were collected at West China Cryo-EM Center in Sichuan University and Cryo-EM Center in Southern University of Science and Technology
(SUSTech) and processed at Duyu High Performance Computing Center in Sichuan University. This work was supported by the National Natural Science
Foundation of China (32100988 to W.Y., T2221004 to S.Y. and Z.S.,
31972916 to Z.S., and 82271190 and 32100965 to L.C.), Science and Technology Department of Sichuan Province (2022ZYD0085 to Z.S., 2021ZYD0080 to
W.Y., and 2020YFQ0055 to P.F.), Ministry of Technology Department of China
grant (2019YFA0508800 to Z.S.), 1.3.5 project for disciplines of excellence,
West China Hospital, Sichuan University (ZYYC20023 to Z.S., ZYGD18027
to P.F.), and Key Research and Development Program of Shandong Province
(2021ZLGX02 to C. Wang).
第一作者机构：[1]Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, SichuanUniversity, Chengdu 610041, Sichuan, China[2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China
共同第一作者：
通讯作者：
通讯机构：[1]Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, SichuanUniversity, Chengdu 610041, Sichuan, China[2]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China
推荐引用方式(GB/T 7714)：
Zhao Chang,Wang Heli,Liu Ying,et al.Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation[J].MOLECULAR CELL.2023,83(17):3171-+.doi:10.1016/j.molcel.2023.07.030.
APA：
Zhao Chang,Wang Heli,Liu Ying,Cheng Lin,Wang Bo...&Shao Zhenhua.(2023).Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.MOLECULAR CELL,83,(17)
MLA：
Zhao Chang,et al."Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation".MOLECULAR CELL 83..17(2023):3171-+
生物学