Schwartz Thue W, Frimurer Thomas M, Holst Birgitte, Rosenkilde Mette M, Elling Christian E
Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, and 7TM Pharma A/S, Hørsholm, Denmark.
Annu Rev Pharmacol Toxicol. 2006;46:481-519. doi: 10.1146/annurev.pharmtox.46.120604.141218.
The multitude of chemically highly different agonists for 7TM receptors apparently do not share a common binding mode or active site but nevertheless act through induction of a common molecular activation mechanism. A global toggle switch model is proposed for this activation mechanism to reconcile the accumulated biophysical data supporting an outward rigid-body movement of the intracellular segments, as well as the recent data derived from activating metal ion sites and tethered ligands, which suggests an opposite, inward movement of the extracellular segments of the transmembrane helices. According to this model, a vertical see-saw movement of TM-VI-and to some degree TM-VII-around a pivot corresponding to the highly conserved prolines will occur during receptor activation, which may involve the outer segment of TM-V in an as yet unclear fashion. Small-molecule agonists can stabilize such a proposed active conformation, where the extracellular segments of TM-VI and -VII are bent inward toward TM-III, by acting as molecular glue deep in the main ligand-binding pocket between the helices, whereas larger agonists, peptides, and proteins can stabilize a similar active conformation by acting as Velcro at the extracellular ends of the helices and the connecting loops.
7TM受体的众多化学性质差异很大的激动剂显然并不共享共同的结合模式或活性位点，但它们通过诱导共同的分子激活机制发挥作用。针对这种激活机制提出了一种全局切换开关模型，以协调积累的支持细胞内片段向外刚体运动的生物物理数据，以及最近来自激活金属离子位点和连接配体的数据，这些数据表明跨膜螺旋的细胞外片段有相反的向内运动。根据该模型，在受体激活过程中，TM-VI以及在某种程度上TM-VII会围绕对应于高度保守脯氨酸的支点进行垂直跷跷板运动，这可能以一种尚不清楚的方式涉及TM-V的外部片段。小分子激动剂可以通过在螺旋之间的主要配体结合口袋深处充当分子胶水来稳定这种提议的活性构象，其中TM-VI和-VII的细胞外片段向内弯曲朝向TM-III，而较大的激动剂、肽和蛋白质可以通过在螺旋的细胞外末端和连接环处充当维可牢尼龙搭扣来稳定类似的活性构象。
