The role of water molecules in phototransduction of retinal proteins and G protein-coupled receptors,Faraday Discussions

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The role of water molecules in phototransduction of retinal proteins and G protein-coupled receptors
Faraday Discussions ( IF 3.3 ) Pub Date : 2017-11-20 , DOI: 10.1039/c7fd00207f
Elena Lesca _{1,

2,

3,

4,

5} , Valérie Panneels _{1,

2,

3,

4,

5} , Gebhard F. X. Schertler _{1,

2,

3,

4,

5}

Affiliation

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.

中文翻译：

水分子在视网膜蛋白和G蛋白偶联受体的光转导中的作用

G蛋白偶联受体（GPCR）是所有真核生物中重要的膜蛋白家族，也是医学干预中非常重要的药物靶标。广泛研究的视觉色素视紫红质是A族GPCR的主要实例。它的发色团配体视网膜共价键合到螺旋七中的赖氨酸，形成质子化的席夫碱。有趣的是，在其他非GPCR视网膜蛋白中也是如此，例如原型光驱动微生物质子泵细菌视紫红质，尽管没有（或只有很远的）系统发育联系。靠近视网膜配体，几个水分子有助于组织功能重要的氢键网络，该网络在光激活过程中会发生重大变化。这种水介导的网络对于其他GPCR的配体结合也至关重要，并且它们在药物发现中变得越来越重要。GPCR还包含部分保守的水介导的氢键网络，该网络稳定了受体的基态，并且该网络的重排导致活性态的稳定。一些水分子在该过程中具有特定作用，以相对于席夫碱适当地定向特定残基，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。虽然这些机制的基本细节仍然缺失，

更新日期：2018-04-17

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