Orthosteric and allosteric modulation of human HCAR2 signaling complex

Chunyou Mao (), Mengru Gao, Shao-Kun Zang, Yanqing Zhu, Dan-Dan Shen, Li-Nan Chen, Liu Yang, Zhiwei Wang, Huibing Zhang, Wei-Wei Wang, Qingya Shen, Yanhui Lu (), Xin Ma () and Yan Zhang ()
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Chunyou Mao: Zhejiang University School of Medicine
Mengru Gao: Jiangnan University
Shao-Kun Zang: Zhejiang University School of Medicine
Yanqing Zhu: Zhejiang University School of Medicine
Dan-Dan Shen: Zhejiang University School of Medicine
Li-Nan Chen: Zhejiang University School of Medicine
Liu Yang: Jiangnan University
Zhiwei Wang: Jiangnan University
Huibing Zhang: Zhejiang University Medical Center
Wei-Wei Wang: Zhejiang University Medical Center
Qingya Shen: Zhejiang University Medical Center
Yanhui Lu: Peking University
Xin Ma: Jiangnan University
Yan Zhang: Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.

Date: 2023
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DOI: 10.1038/s41467-023-43537-z

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