What Makes GPCRs from Different Families Bind to the Same Ligand?
What Makes GPCRs from Different Families Bind to the Same Ligand?
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DOI：
10.3390/biom12070863
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发表时间：
2022-06-21
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
G蛋白偶联受体(GPCRs)是细胞表面最大的一类受体蛋白，在信号转导中具有重要作用，常作为治疗药物靶点。随着GPCRs三维结构和GPCR与配体相互作用的公开数据的快速增长，在配体发现的初始阶段，计算预测GPCRs与配体的结合成为高通量筛选和其他实验方法的一个令人信服的选择。在这项工作中，我们开始从计算上揭示和理解单个配体与几个不同家族的GPCRs的结合。对与同一配体结合的GPCRs的三维结构比较显示，局部3D结构相似，并且这些区域经常与结合口袋的位置重叠。这些口袋被发现是相似的(基于使用apoC的主链几何形状和侧链取向)，并且它们与口袋的静电性能呈正相关。此外，口袋越相似，与口袋结合的配体就越有可能与相似的残基相互作用，具有相似的构象，并在口袋上产生类似的结合亲和力。这些发现可用于改进蛋白质功能推断、药物再利用和药物毒性预测，加速新药的开发。
G protein-coupled receptors (GPCRs) are the largest class of cell-surface receptor proteins with important functions in signal transduction and often serve as therapeutic drug targets. With the rapidly growing public data on three dimensional (3D) structures of GPCRs and GPCR-ligand interactions, computational prediction of GPCR ligand binding becomes a convincing option to high throughput screening and other experimental approaches during the beginning phases of ligand discovery. In this work, we set out to computationally uncover and understand the binding of a single ligand to GPCRs from several different families. Three-dimensional structural comparisons of the GPCRs that bind to the same ligand revealed local 3D structural similarities and often these regions overlap with locations of binding pockets. These pockets were found to be similar (based on backbone geometry and side-chain orientation using APoc), and they correlate positively with electrostatic properties of the pockets. Moreover, the more similar the pockets, the more likely a ligand binding to the pockets will interact with similar residues, have similar conformations, and produce similar binding affinities across the pockets. These findings can be exploited to improve protein function inference, drug repurposing and drug toxicity prediction, and accelerate the development of new drugs.
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