2. Academic Validation
  3. Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation

Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation

  • Mol Cell. 2023 Aug 11;S1097-2765(23)00605-6. doi: 10.1016/j.molcel.2023.07.030.
Chang Zhao 1,  Heli Wang 1,  Ying Liu 2,  Lin Cheng 3,  Bo Wang 2,  Xiaowen Tian 1,  Hong Fu 1,  Chao Wu 1,  Ziyan Li 1,  Chenglong Shen 1,  Jingjing Yu 1,  Shengyong Yang 1,  Hongbo Hu 4,  Ping Fu 2,  Liang Ma 5,  Chuanxin Wang 6,  Wei Yan 7,  Zhenhua Shao 8
Affiliations

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 Gi/o protein or β-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.

Keywords

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

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