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.

中文翻译：

---

7TM受体激活的分子机制-全局拨动开关模型。

显然，许多针对7TM受体的化学上高度不同的激动剂并不共享共同的结合模式或活性位点，但通过诱导共同的分子激活机制起作用。针对这种激活机制，提出了一个全局拨动开关模型，以协调积累的支持细胞内区段向外刚性运动的生物物理数据，以及源自激活金属离子位点和束缚配体的最新数据，这表明情况相反。跨膜螺旋的细胞外节段的向内运动。根据此模型，在受体激活期间，TM-VI-以及某种程度上的TM-VII-围绕对应于高度保守的脯氨酸的枢轴将发生垂直跷跷板运动，可能尚不明确，可能涉及TM-V的外部部分。小分子激动剂可以通过在螺旋之间的主要配体结合口袋中深处充当分子胶，使TM-VI和-VII的细胞外区段向内弯曲向TM-III，从而使这种提议的活性构象稳定。激动剂，肽和蛋白质可通过在螺旋和连接环的细胞外端充当维可牢尼龙搭扣来稳定相似的活性构象。