Institute for Neuroscience and Pharmacology, The Panum Institute, Copenhagen University, Copenhagen N, Denmark.
Curr Mol Pharmacol. 2009 Jun;2(2):140-8. doi: 10.2174/1874467210902020140.
During the two past decades tremendous effort has been put into uncovering the activation mechanism of 7TM receptors. The majority of such studies have focused on the major binding pocket, comprised of transmembrane segments (TM) -III through -VII, as most non-peptide and peptide ligands, in addition to biogenic amines and retinal a.m.o. bind to residues in this region. Consequently the major helical movements occur here during activation, as described recently in the Global Toggle Switch Model for Family A (also known as rhodopsin-like) members of the 7TM receptors. As a result, the minor binding pocket, comprised of TM-I, -II and, in part, -III and -VII, has received much less attention. With a few exceptions, such as the highly conserved Asp in position II:10/2.50, the residues in this region have generally been considered insignificant with regard to receptor activation. However, accumulating evidence emphasize that this is not the case. In this review, we focus on TM-II with an emphasis on position II:20/2.60, and present data from structure-activity studies on a range of Family A 7TM receptors including chemokine, ghrelin and melanocortin receptors in addition to the orphan EBI2 suggesting that TM-II has important functions for both ligand-dependent and -independent activation of 7TM receptors.
在过去的二十年中，人们付出了巨大的努力来揭示 7TM 受体的激活机制。大多数此类研究都集中在主要结合口袋上，该口袋由跨膜片段 (TM)-III 至 -VII 组成，因为大多数非肽和肽配体，除了生物胺和视网膜 a.m.o.，都与该区域的残基结合。因此，正如最近在家族 A（也称为视紫红质样）7TM 受体的全局 Toggle Switch 模型中所述，在激活过程中主要发生在这里的螺旋运动。结果，由 TM-I、-II 以及部分 -III 和 -VII 组成的次要结合口袋受到的关注要少得多。除了少数例外，例如位置 II:10/2.50 处高度保守的 Asp，该区域的残基通常被认为与受体激活无关紧要。然而，越来越多的证据强调事实并非如此。在这篇综述中，我们重点关注 TM-II，特别是位置 II:20/2.60，并介绍了一系列结构活性研究的数据，这些研究涉及家族 A 7TM 受体，包括趋化因子、胃饥饿素和黑皮质素受体，以及孤儿 EBI2，这表明 TM-II 对于配体依赖性和非依赖性 7TM 受体的激活具有重要功能。
