Teeter M M, Froimowitz M, Stec B, DuRand C J
Eugene F. Merkert Chemistry Center, Department of Chemistry, Boston College, Chestnut Hill 02167.
J Med Chem. 1994 Sep 2;37(18):2874-88. doi: 10.1021/jm00044a008.
We present the first model of dopamine D2 receptor transmembrane helices constructed directly from the bacteriorhodopsin (bR) coordinates derived from two-dimensional electron diffraction experiments. We have tested this model by its ability to accommodate rigid agonist and semirigid antagonist molecules which were docked into the putative binding pocket with stabilizing interactions. The model is consistent with structure-activity relationships of agonists and antagonists that interact with the receptor. It also illuminates data on a Na+ site for regulation of receptor function. The plausibility of the model is increased by its consistency with many mutagenesis studies on G protein-coupled receptors. Further, this model provides a basis to suggest testable molecular mechanisms for changes in the D2 conformational states for high- and low-affinity binding and signal transduction. Changes in the conformational state of the receptor are hypothesized to be due partly to movement of helix 7. In contrast to the model presented here, other published models were built using ideal helical structures or following the sense of the bacteriorhodopsin structure rather than the actual available coordinates. The presented model for the dopamine G protein-coupled receptor can be reconciled with the recent rhodopsin projection structure (Schertler, G. F. X.; Villa, C.; Henderson, R. Projection Structure of Rhodopsin.
我们展示了首个直接从二维电子衍射实验获得的细菌视紫红质（bR）坐标构建的多巴胺D2受体跨膜螺旋模型。我们通过该模型容纳刚性激动剂和半刚性拮抗剂分子的能力对其进行了测试，这些分子通过稳定相互作用对接至假定的结合口袋中。该模型与与受体相互作用的激动剂和拮抗剂的构效关系一致。它还阐明了关于调节受体功能的Na+位点的数据。该模型与许多关于G蛋白偶联受体的诱变研究结果一致，这增加了其合理性。此外，该模型为提出关于D2高亲和力和低亲和力结合以及信号转导构象状态变化的可测试分子机制提供了基础。假设受体构象状态的变化部分归因于螺旋7的移动。与本文提出的模型不同，其他已发表的模型是使用理想螺旋结构构建的，或者遵循细菌视紫红质结构的方向而非实际可用坐标。所提出的多巴胺G蛋白偶联受体模型可以与最近的视紫红质投影结构（舍尔特勒，G.F.X.；维拉，C.；亨德森，R.视紫红质的投影结构）相协调。
