Bosch L, Iarriccio L, Garriga P
Centre de Biotecnologia Molecular (CEBIM), Departament d'Enginyeria Química, Universitat Politècnica de Catalunya, 08222 Terrassa, Catalonia, Spain.
Curr Pharm Des. 2005;11(17):2243-56. doi: 10.2174/1381612054367436.
G-protein-coupled receptors (GPCR) are a major class of membrane proteins belonging to a continuously growing superfamily. These receptors play a critical role in signal transduction, and are among the most important pharmacological drug targets. The first structural model for the GPCR superfamily was the bacterial protein bacteriorhodopsin with its characteristic seven transmembrane (TM) helical architecture. The visual photoreceptor rhodopsin is a better model for GPCR, and the recent elucidation of the crystal structure of bovine rhodopsin has renewed the interest in this receptor as a template for molecular modeling of other GPCR, particularly for the implications in ligand design and drug discovery. In this work different specific structural elements of rhodopsin are reviewed and the role of conserved motifs, like those associated with receptor function, is analyzed. The specific characteristics of the membrane-embedded ligand-binding domain are described. Other aspects, like receptor dimerization or the constitutive activity mechanism, are also outlined. The importance of acquiring knowledge of the active conformation of the receptor by means of both modeling and experimental techniques is also highlighted. In this regard, the model of the activated form of rhodopsin is currently under investigation, and it may provide useful information for pharmaceutical design. Rhodopsin will continue to be a widely used model for GPCR but rhodopsin-based approaches have to be complemented by other theoretical and experimental approaches -while waiting for the crystal structure of other members of the superfamily- if these want to be successfully used for drug discovery.
G蛋白偶联受体（GPCR）是一大类膜蛋白，属于一个不断扩大的超家族。这些受体在信号转导中起关键作用，是最重要的药理学药物靶点之一。GPCR超家族的第一个结构模型是细菌蛋白细菌视紫红质，其具有特征性的七跨膜（TM）螺旋结构。视觉光感受器视紫红质是GPCR的一个更好模型，最近牛视紫红质晶体结构的阐明重新激发了人们对该受体作为其他GPCR分子建模模板的兴趣，特别是在配体设计和药物发现方面的意义。在这项工作中，我们综述了视紫红质的不同特定结构元件，并分析了保守基序的作用，如那些与受体功能相关的基序。描述了膜嵌入配体结合结构域的特定特征。还概述了其他方面，如受体二聚化或组成性活性机制。还强调了通过建模和实验技术获取受体活性构象知识的重要性。在这方面，视紫红质活化形式的模型目前正在研究中，它可能为药物设计提供有用信息。视紫红质将继续是GPCR广泛使用的模型，但基于视紫红质的方法必须辅以其他理论和实验方法——在等待超家族其他成员的晶体结构时——如果这些方法想要成功用于药物发现的话。
