Goddard William A, Abrol Ravinder
Materials and Process Simulation Center, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.
J Nutr. 2007 Jun;137(6 Suppl 1):1528S-1538S; discussion 1548S. doi: 10.1093/jn/137.6.1528S.
We summarize here recent progress in predicting the 3-dimensional (3D) structure of G protein-coupled receptors (GPCR) and in predicting the binding sites for various agonists and antagonists. These receptors play a critical role in cell communications (dopamine, histamine, epinephrine, and serotonin) and in sensing the outside world (vision, smell, taste, and pain). There are no experimental 3D structures available for human GPCR despite their vital function and importance as therapeutic targets. Indeed, considering every form of life, there is an experimental structure for only 1 GPCR: bovine rhodopsin. Consequently, we developed the MembStruk method to predict the 3D structure without using homology. We then validated our predicted structures by using them to predict their binding sites and binding energies for strongly binding agonists and antagonists. The results were in excellent agreement with available binding and mutation experiments. We will summarize the results for adrenergic receptors, dopamine receptors, chemokine receptors, muscarinic acetylcholine receptors, and a tetrapeptide receptor (mas-related gene C11).
我们在此总结近期在预测G蛋白偶联受体（GPCR）的三维（3D）结构以及预测各种激动剂和拮抗剂结合位点方面取得的进展。这些受体在细胞通讯（多巴胺、组胺、肾上腺素和血清素）以及感知外部世界（视觉、嗅觉、味觉和疼痛）中起着关键作用。尽管人类GPCR具有重要功能且作为治疗靶点具有重要意义，但目前尚无其实验性3D结构。事实上，考虑到所有生命形式，仅有1种GPCR有实验性结构：牛视紫红质。因此，我们开发了MembStruk方法，无需使用同源性来预测3D结构。然后，我们通过利用预测结构来预测其与强结合激动剂和拮抗剂的结合位点及结合能，对预测结构进行了验证。结果与现有的结合和突变实验结果高度吻合。我们将总结肾上腺素能受体、多巴胺受体、趋化因子受体、毒蕈碱型乙酰胆碱受体以及一种四肽受体（mas相关基因C11）的研究结果。
