Department of Human Genetics, Translational Medicine Division, Research Branch, Sidra Medicine, Doha 26999, Qatar.
Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar.
Molecules. 2022 Jun 23;27(13):4037. doi: 10.3390/molecules27134037.
Obesity is a chronic disease with increasing cases among children and adolescents. Melanocortin 4 receptor (MC4R) is a G protein-coupled transporter involved in solute transport, enabling it to maintain cellular homeostasis. MC4R mutations are associated with early-onset severe obesity, and the identification of potential pathological variants is crucial for the clinical management of patients with obesity. A number of mutations have been reported in MC4R that are responsible for causing obesity and related complications. Delineating these mutations and analyzing their effect on MC4R's structure will help in the clinical intervention of the disease condition as well as designing potential drugs against it. Sequence-based pathogenicity and structure-based protein stability analyses were conducted on naturally occurring variants. We used computational tools to analyze the conservation of these mutations on MC4R's structure to map the structural variations. Detailed structural analyses were carried out for the active site mutations (i.e., D122N, D126Y, and S188L) and their influence on the binding of calcium and the agonist or antagonist. We performed molecular dynamics (MD) simulations of the wild-type and selected mutations to delineate the conformational changes, which provided us with possible reasons for MC4R's instability in these mutations. This study provides insight into the potential direction toward understanding the molecular basis of MC4R dysfunction in disease progression and obesity.
肥胖是一种慢性疾病，在儿童和青少年中的发病率不断上升。黑皮质素 4 受体（MC4R）是一种参与溶质转运的 G 蛋白偶联转运体，使其能够维持细胞内稳态。MC4R 突变与早发性重度肥胖有关，鉴定潜在的病理性变异对肥胖症患者的临床管理至关重要。已经报道了许多导致肥胖和相关并发症的 MC4R 突变。阐明这些突变并分析它们对 MC4R 结构的影响有助于对疾病状况进行临床干预，并设计针对该疾病的潜在药物。对天然存在的变异进行基于序列的致病性和基于结构的蛋白质稳定性分析。我们使用计算工具分析这些突变在 MC4R 结构上的保守性，以绘制结构变异图。对活性位点突变（即 D122N、D126Y 和 S188L）及其对钙和激动剂或拮抗剂结合的影响进行了详细的结构分析。我们对野生型和选定突变进行了分子动力学（MD）模拟，以描绘构象变化，这为我们提供了这些突变中 MC4R 不稳定性的可能原因。这项研究深入了解了理解 MC4R 功能障碍在疾病进展和肥胖中的分子基础的潜在方向。
