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Orthosteric and allosteric modulation of human HCAR2 signaling complex.

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.

SUBMITTER: Mao C

PROVIDER: S-EPMC10665550 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Orthosteric and allosteric modulation of human HCAR2 signaling complex.

Mao Chunyou C Gao Mengru M Zang Shao-Kun SK Zhu Yanqing Y Shen Dan-Dan DD Chen Li-Nan LN Yang Liu L Wang Zhiwei Z Zhang Huibing H Wang Wei-Wei WW Shen Qingya Q Lu Yanhui Y Ma Xin X Zhang Yan Y

Nature communications 20231122 1

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 ...[more]

PMID: 37993467

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Project description:Allosteric modulators (AMs) are considered as a perpetual hotspot in research for their higher selectivity and various effects on orthosteric ligands (OL). They are classified in terms of their functionalities as positive, negative, or silent allosteric modulators (PAM, NAM, or SAM, respectively). In the present work, 11 pairs of three-dimensional (3D) structures of receptor-orthosteric ligand and receptor-orthosteric ligand-allosteric modulator complexes have been collected for the studies, including three different systems: GPCR, enzyme, and ion channel. Molecular dynamics (MD) simulations are applied to quantify the dynamic interactions in both the orthosteric and allosteric binding pockets and the structural fluctuation of the involved proteins. Our results showed that MD simulations of moderately large molecules or peptides undergo insignificant changes compared to crystal structure results. Furthermore, we also studied the conformational changes of receptors that bound with PAM and NAM, as well as the different allosteric binding sites in a receptor. There should be no preference for the position of the allosteric binding pocket after comparing the allosteric binding pockets of these three systems. Finally, we aligned four distinct β2 adrenoceptor structures and three N-methyl-d-aspartate receptor (NMDAR) structures to investigate conformational changes. In the β2 adrenoceptor systems, the aligned results revealed that transmembrane (TM) helices 1, 5, and 6 gradually increased outward movement from an enhanced inactive state to an improved active state. TM6 endured the most significant conformational changes (around 11 Å). For NMDAR, the bottom section of NMDAR's ligand-binding domain (LBD) experienced an upward and outward shift during the gradually activating process. In conclusion, our research provides insight into receptor-orthosteric ligand-allosteric modulator studies and the design and development of allosteric modulator drugs using MD simulation.

Dataset Information

Orthosteric and allosteric modulation of human HCAR2 signaling complex.

Publications

Orthosteric and allosteric modulation of human HCAR2 signaling complex.

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