Ligand Recognition and Activation Mechanism of the Alicarboxylic Acid Receptors

IF 4.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Biology Pub Date : 2024-09-19 DOI:10.1016/j.jmb.2024.168795

Yanru Liu , Ziwei Zhou , Fenghui Guan , Zhen Han , Cheng Zhu , Sheng Ye , Xuekui Yu , Anna Qiao

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Abstract

Endogenous ligands for alicarboxylic acid receptors are important metabolic intermediates that play a significant role in regulating body energy and maintaining homeostasis. However, the molecular mechanism of alicarboxylate ligand-mediated counterpart receptors is currently unclear. We resolve the active state structure of HCA2-niacin, and the structural analysis explains the mechanism of niacin selectivity in the alicarboxylic acid receptors family. Homology modeling, molecular dynamics simulation and mutagenesis experiments reveal different ligand recognition modes and activation mechanisms of the alicarboxylic acid receptors, analyze the flexibility of the binding pocket and elucidate the important role of disulfide bonds on receptor activation and ligand binding. These more detailed molecular mechanisms further elucidate the relevant mechanisms of human metabolism and provide key clues for subsequent drug development of alicarboxylic acid receptors.

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羧酸受体的配体识别和激活机制。

羧酸受体的内源配体是重要的代谢中间产物，在调节机体能量和维持体内平衡方面发挥着重要作用。然而，羧酸配体介导对应受体的分子机制目前尚不清楚。我们解析了 HCA2-烟酸的活性状态结构，并通过结构分析解释了烟酸受体家族中烟酸选择性的机制。同源建模、分子动力学模拟和诱变实验揭示了羧酸受体的不同配体识别模式和激活机制，分析了结合口袋的灵活性，阐明了二硫键对受体激活和配体结合的重要作用。这些更详细的分子机制进一步阐明了人体代谢的相关机制，为后续的羧酸受体药物开发提供了关键线索。

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来源期刊

Journal of Molecular Biology 生物-生化与分子生物学

CiteScore

11.30

自引率

1.80%

发文量

412

审稿时长

28 days

期刊介绍： Journal of Molecular Biology (JMB) provides high quality, comprehensive and broad coverage in all areas of molecular biology. The journal publishes original scientific research papers that provide mechanistic and functional insights and report a significant advance to the field. The journal encourages the submission of multidisciplinary studies that use complementary experimental and computational approaches to address challenging biological questions. Research areas include but are not limited to: Biomolecular interactions, signaling networks, systems biology; Cell cycle, cell growth, cell differentiation; Cell death, autophagy; Cell signaling and regulation; Chemical biology; Computational biology, in combination with experimental studies; DNA replication, repair, and recombination; Development, regenerative biology, mechanistic and functional studies of stem cells; Epigenetics, chromatin structure and function; Gene expression; Membrane processes, cell surface proteins and cell-cell interactions; Methodological advances, both experimental and theoretical, including databases; Microbiology, virology, and interactions with the host or environment; Microbiota mechanistic and functional studies; Nuclear organization; Post-translational modifications, proteomics; Processing and function of biologically important macromolecules and complexes; Molecular basis of disease; RNA processing, structure and functions of non-coding RNAs, transcription; Sorting, spatiotemporal organization, trafficking; Structural biology; Synthetic biology; Translation, protein folding, chaperones, protein degradation and quality control.