G-蛋白偶联受体GPR120分子模建研究

新的长链脂肪酸受体G-蛋白偶联受体120 (G-protein-coupled receptor120, GPR120)是2型糖尿病的潜在治疗靶标. 由于其晶体结构迄今尚未获得, 成为基于结构的新药设计的瓶颈. 首先, 以人体β2肾上腺能素受体(human β2 adrenergic receptor, β2AR)晶体结构为模板, 通过同源模建方法构建GPR120三维结构, 对整个体系进行包膜的分子动力学模拟. 然后采用分子对接技术模建了GPR120的小分子激动剂GW9508与GPR120的相互作用模型, 发现了受体分子识别的关键性残基, 为开展定点突变实验提供了指导意义. 所建模型为研究受体与配体作用提供了合理的初始结构, 此方法也适用于其他G蛋白偶联受体的分子模建.

G-Protein-Coupled Receptor 120-GPR120: Molecular Modeling Studies

G-protein-coupled receptor 120 (GPR120), which functions as a new receptor for long chain free fatty acids, may play a role as a potential therapeutic target for type 2 diabetes mellitus. The three-dimensional (3D) structure of GPR120 is experimentally unavailable to date, however, leading to difficulty in the structure-based drug design. Based on the X-ray crystal structure of β2 adrenergic receptor, a homology model of the GPR120 was constructed, then, molecular-dynamics (MD) simulations were carried out for the entire system. The GPR120 ligand agonist GW9508 was docked into the optimized model, and the critical amino acid residues for binding were identified, which was very important for further site-directed mutagenesis study. The constructed models should provide a good starting point for further characterization of the binding models for GPR120 ligands. Furthermore, the method developed herein will be applicable to build other GPCRs.