<br>MUG：GPCR 亚家族 A17 受体的突变概述,Computational and Structural Biotechnology Journal

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MUG：GPCR 亚家族 A17 受体的突变概述
Computational and Structural Biotechnology Journal ( IF 4.4 ) Pub Date : 2022-12-21 , DOI: 10.1016/j.csbj.2022.12.031
Ana B Caniceiro _{1,

2} , Beatriz Bueschbell _{1,

3} , Carlos A V Barreto _{1,

3} , António J Preto _{1,

3} , Irina S Moreira _{1,

4}

Affiliation

G 蛋白偶联受体（GPCR）通过涉及其激活的一般机制介导多个信号通路，维护导致负责细胞质作用和进一步调节的分子释放的一系列事件。这些生理功能可因 GPCR 基因突变而严重改变。GPCR 亚家族 A17（多巴胺、血清素、肾上腺素能和微量胺受体）与神经退行性疾病直接相关，因此探索这些系统的已知突变及其对结构和功能的影响至关重要。构建了一个全面而详细的计算框架 - MUG （突变理解 GPCR） - 说明了已报道的关键突变及其对 GPCRs 亚家族 A17 受体的影响。我们探讨了总体上和亚家族 A17 不同家族中发生的突变类型，以及它们在受体内的位置和对受体功能的潜在影响。考虑到突变残基的致病性，进一步分析了突变的残基。结果揭示了 GPCR 亚家族 A17 结构中高度多样化的突变，引起了人们对保守残基和结构域中大量突变的关注。突变残基通常是富集在配体结合口袋和已知激活微结构域的疏水残基，这可能导致受体功能中断。MUG 作为交互式 Web 应用程序可用于此数据集的管理和可视化。我们期望这个交互式数据库有助于探索 GPCR 突变、它们的影响以及它们的家族和受体特异性作用，构成在原子水平上阐明其结构和分子的第一步。

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MUG: A mutation overview of GPCR subfamily A17 receptors

G protein-coupled receptors (GPCRs) mediate several signaling pathways through a general mechanism that involves their activation, upholding a chain of events that lead to the release of molecules responsible for cytoplasmic action and further regulation. These physiological functions can be severely altered by mutations in GPCR genes. GPCRs subfamily A17 (dopamine, serotonin, adrenergic and trace amine receptors) are directly related with neurodegenerative diseases, and as such it is crucial to explore known mutations on these systems and their impact in structure and function. A comprehensive and detailed computational framework - MUG (Mutations Understanding GPCRs) - was constructed, illustrating key reported mutations and their effect on receptors of the subfamily A17 of GPCRs. We explored the type of mutations occurring overall and in the different families of subfamily A17, as well their localization within the receptor and potential effects on receptor functionality. The mutated residues were further analyzed considering their pathogenicity. The results reveal a high diversity of mutations in the GPCR subfamily A17 structures, drawing attention to the considerable number of mutations in conserved residues and domains. Mutated residues were typically hydrophobic residues enriched at the ligand binding pocket and known activating microdomains, which may lead to disruption of receptor function. MUG as an interactive web application is available for the management and visualization of this dataset. We expect that this interactive database helps the exploration of GPCR mutations, their influence, and their familywise and receptor-specific effects, constituting the first step in elucidating their structures and molecules at the atomic level.

更新日期：2022-12-21

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