Ahuja Shivani, Smith Steven O
Department of Physics and Astronomy and Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
Trends Pharmacol Sci. 2009 Sep;30(9):494-502. doi: 10.1016/j.tips.2009.06.003. Epub 2009 Sep 3.
The activation mechanism of G protein-coupled receptors has presented a puzzle that finally may be close to solution. These receptors have a relatively simple architecture consisting of seven transmembrane helices that contain just a handful of highly conserved amino acids, yet they respond to light and a range of chemically diverse ligands. Recent NMR structural studies on the active metarhodopsin II intermediate of the visual receptor rhodopsin, along with the recent crystal structure of the apoprotein opsin, have revealed multiple structural elements or 'switches' that must be simultaneously triggered to achieve full activation. The confluence of several required structural changes is an example of "coincidence counting", which is often used by nature to regulate biological processes. In ligand-activated G protein-coupled receptors, the presence of multiple switches may provide an explanation for the differences between full, partial and inverse agonists.
G蛋白偶联受体的激活机制一直是个谜题，如今或许终于接近答案了。这些受体结构相对简单，由七个跨膜螺旋组成，仅包含少数高度保守的氨基酸，但它们能对光以及一系列化学性质各异的配体作出反应。近期针对视觉受体视紫红质的活性视紫红质II中间体的核磁共振结构研究，以及脱辅基蛋白视蛋白的晶体结构，揭示了多个必须同时触发才能实现完全激活的结构元件或“开关”。几种所需结构变化的同时出现是“巧合计数”的一个例子，自然界常利用这种方式来调节生物过程。在配体激活的G蛋白偶联受体中，多个开关的存在或许能解释完全激动剂、部分激动剂和反向激动剂之间的差异。
