Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation

Chang Zhao; Heli Wang; Ying Liu; Lin Cheng; Bo Wang; Xiaowen Tian; Hong Fu; Chao Wu; Ziyan Li; Chenglong Shen; Jingjing Yu; Shengyong Yang; Hongbo Hu; Ping Fu; Liang Ma; Chuanxin Wang; Wei Yan; Zhenhua Shao

doi:10.1016/j.molcel.2023.07.030

Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation

Mol Cell. 2023 Sep 7;83(17):3171-3187.e7. doi: 10.1016/j.molcel.2023.07.030. Epub 2023 Aug 18.

Authors

Chang Zhao¹, Heli Wang¹, Ying Liu², Lin Cheng³, Bo Wang², Xiaowen Tian¹, Hong Fu¹, Chao Wu¹, Ziyan Li¹, Chenglong Shen¹, Jingjing Yu¹, Shengyong Yang¹, Hongbo Hu⁴, Ping Fu², Liang Ma⁵, Chuanxin Wang⁶, Wei Yan⁷, Zhenhua Shao⁸

Affiliations

¹ Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China.
² Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
³ Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610000, Sichuan, China.
⁴ Department of Rheumatology and Immunology, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, Sichuan, China.
⁵ Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: liang_m@scu.edu.cn.
⁶ Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, Shandong, China. Electronic address: cxwang@sdu.edu.cn.
⁷ Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China. Electronic address: weiyan2018@scu.edu.cn.
⁸ Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China. Electronic address: zhenhuashao@scu.edu.cn.

PMID: 37597514
DOI: 10.1016/j.molcel.2023.07.030

Abstract

Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating G_i/o protein or β-arrestin effectors. Here, we characterize compound 9n as a G_i-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-G_i pathway. Furthermore, four structures of HCAR2-G_i 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.

Keywords: BHB; GPCR; HCAR2; allosteric modulation; anti-inflamation; biased allosteric modulator; cryo-EM; ketone body receptor; niacin; structural biology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Animals
Colitis* / chemically induced
Colitis* / drug therapy
Colitis* / metabolism
GTP-Binding Protein alpha Subunits, Gi-Go
Inflammation / drug therapy
Ketone Bodies
Mice
Niacin / pharmacology
Receptors, G-Protein-Coupled* / agonists
Receptors, G-Protein-Coupled* / metabolism

Substances

GTP-Binding Protein alpha Subunits, Gi-Go
Ketone Bodies
Niacin
Hcar2 protein, mouse
Receptors, G-Protein-Coupled