Division of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
Faraday Discuss. 2018 Apr 17;207(0):27-37. doi: 10.1039/c7fd00207f.
G protein coupled receptors (GPCRs) are a key family of membrane proteins in all eukaryotes and also very important drug targets for medical intervention. The extensively studied visual pigment rhodopsin is a prime example of a family A GPCR. Its chromophore ligand retinal is covalently linked to a lysine in helix seven forming a protonated Schiff base. Interestingly, this is the same situation in other-non-GPCR-retinal proteins, like the prototype light-driven microbial proton pump bacteriorhodopsin, albeit there is no (or only a very remote) phylogenetical link. Close to the retinal ligand, several water molecules help to organise a functionally important hydrogen bond network that undergoes significant changes during photo-activation. Such water-mediated networks are also critical for ligand binding of other GPCRs and they are becoming increasingly important in drug discovery. GPCRs also contain a partially conserved water mediated hydrogen bond network that stabilises the ground state of the receptor, and rearrangement of this network leads to the stabilization of the active state. Some water molecules have a specific role in this process to appropriately orient specific residues relative to the Schiff base, and to modulate the fine structure of the transmembrane bundle, particularly near the intracellular G protein binding site. While the atomic details of these mechanisms are still missing, the recent developments in free electron lasers (FELs) are enabling us to begin to observe the changes in waters and relevant side chains shortly after photo activation at an unprecedented level of spatial and temporal resolution.
G 蛋白偶联受体（GPCRs）是所有真核生物中一类重要的膜蛋白家族，也是医学干预的重要药物靶点。广泛研究的视觉色素视紫红质是 A 族 GPCR 的一个典型例子。其发色团配体视黄醛与螺旋七中的赖氨酸共价连接，形成质子化的席夫碱。有趣的是，这种情况在其他非 GPCR-视黄醛蛋白中也存在，如原型光驱动微生物质子泵菌视紫红质，尽管它们之间没有（或只有非常遥远的）系统发育联系。在视黄醛配体附近，有几个水分子有助于组织一个功能上重要的氢键网络，该网络在光激活过程中会发生显著变化。这种水介导的网络对于其他 GPCR 配体的结合也至关重要，它们在药物发现中变得越来越重要。GPCR 还包含一个部分保守的水介导氢键网络，该网络稳定受体的基态，而该网络的重排导致活性状态的稳定。一些水分子在这个过程中具有特定的作用，适当地将特定残基相对于席夫碱定向，并调节跨膜束的精细结构，特别是在细胞内 G 蛋白结合位点附近。虽然这些机制的原子细节仍然缺失，但自由电子激光器（FELs）的最新发展使我们能够开始以空前的时空分辨率水平观察光激活后短时间内水中和相关侧链的变化。
