G protein-coupled receptors (GPCRs) are key membrane-embedded receptor proteins, with critical roles in cellular signal transduction. In the era of precision medicine, understanding the role of natural variants on GPCR function is critical, especially from a pharmacogenomics viewpoint. Studies involved in mapping variants to GPCR structures are briefly reviewed here. The endocannabinoid system involving the central nervous system (CNS), the human cannabinoid receptor 1 (CB1), is an important drug target and its variability has implications for disease susceptibility and altered drug and pain response. We have carried out a computational study to map deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) to CB1. CB1 mutations were computationally evaluated from neutral to deleterious, and the top twelve deleterious mutations, with structural information, were found to be either close to the ligand binding region or the G-protein binding site. We have mapped these to the active and inactive CB1 X-ray crystallographic structures to correlate variants with available phenotypic information. We have also carried out molecular dynamics simulations to functionally characterize four selected mutants.

中文翻译：

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GPCR功能变异的结构生物信息学分析。

G蛋白偶联受体（GPCR）是关键的膜嵌入受体蛋白，在细胞信号转导中起关键作用。在精密医学时代，了解自然变异对GPCR功能的作用至关重要，尤其是从药物基因组学的角度来看。这里简要回顾了将变体映射到GPCR结构的研究。涉及中枢神经系统（CNS）的内源性大麻素系统，人类大麻素受体1（CB1）是重要的药物靶标，其可变性对疾病易感性以及药物和疼痛反应的改变有影响。我们进行了一项计算研究，以将有害的非同义单核苷酸多态性（nsSNPs）映射到CB1。通过计算评估了CB1突变（从中性到有害），以及排名前12位的有害突变，具有结构信息的分子被发现靠近配体结合区或G蛋白结合位点。我们已经将它们映射到活性和非活性CB1 X射线晶体学结构，以将变体与可用的表型信息相关联。我们还进行了分子动力学模拟，以功能表征四个选定的突变体。