Structures of the first intermediates of the visual cascade

视觉级联第一个中间体的结构

• 批准号: 15498772
• 负责人: Professor Dr. Peter Entel (†)
• 金额: --
• 依托单位: Fakultät für Chemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2005
• 资助国家: 德国
• 起止时间: 2004-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/15498772?language=en
• 关键词: Structures; first; intermediates; visual; cascade

G-protein-coupled receptors (GPCRs) constitute the largest family of heptahelical transmembrane proteins. Essential for signal transduction across cell membranes they affect a broad variety of physiological processes. Rhodopsin is a prototypical GPCR which is responsible for scotopic vision in vertebrate species. lt is also the only GPCR for which the crystal structure has been determined providing in atomic detail the structure of its ligand, 11-cis-retinal, and how it fits into the protein. Elucidation of the mechanism, by which ligand excitation is transformed into rhodopsin activation and coupling to the G-protein may become exemplary for the structure and function of other members of the GPCR group.Despite the information gained from the resting state of rhodopsin the ensuing intermediates of the visual cascade remain an enigma. For bathorhodopsin which is the intermediate directly following photoexcitation a crystal structure exists, but has not been made public. For the Meta 1 intermediate low-resolution cryoelectron microscopic images have published. The aim of the present proposal is threefold: verify, and if necessary improve the reported structures, especially with respect to the ligand conformation, by employing high-quality ab initio methods supported, where necessary and possible, by classical force field methods; secondly, develop structural models for the batho intermediate by performing ab initio molecular dynamics an both the ground and the excited state potential energy surfaces. Finally, structural models for the later intermediates will be developed based an the available structures and indirect evidence.On the basis of these structures the properties of the intermediates will be studied in other projects, and dynamical models will be developed to arrive at a comprehensive description of the initial stages of the visual cascade.

G蛋白偶联受体（GPCR）是最大的七螺旋跨膜蛋白家族。对于跨细胞膜的信号转导至关重要，它们影响各种各样的生理过程。视紫红质是一种典型的GPCR，其负责脊椎动物物种中的暗视觉。它也是唯一的GPCR的晶体结构已被确定，提供原子细节的结构，其配体，11-顺式-视网膜，以及它如何融入蛋白质。阐明的机制，通过该配体激发转化为视紫红质激活和耦合到G-蛋白可能成为示范的结构和功能的其他成员的GPCR group.Despite信息获得的视紫红质的静止状态，随后的中间体的视觉级联反应仍然是一个谜。对于直接在光激发之后的中间体bathorhodopsin，存在晶体结构，但尚未公开。对于Meta 1的中间低分辨率冷冻电子显微镜图像已经发表。本提案的目的是三重的：验证，并在必要时改善报告的结构，特别是关于配体构象，采用高质量的从头计算方法支持，在必要和可能的情况下，由经典力场方法;其次，开发结构模型的batho中间体进行从头计算分子动力学的地面和激发态势能面。最后，我们将根据现有的结构和间接证据，为后来的中间体建立结构模型，并在这些结构的基础上，在其他项目中研究中间体的性质，并建立动力学模型，以全面描述视觉级联的初始阶段。