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: 5385579
• 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: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2005-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5385579?language=en
• 关键词: Structures; first; intermediates; visual; cascade

Rhodopsin, the photoreceptor for dim light vision in the vertebrate eye, is a so-called G-protein coupled receptor or GPCR. The primary step of the visual cascade of rhodopsin is the isomerization from cis to trans of the C11=C12 double bond of retinal, the chromophore of rhodopsin, to form the bathorhodopsin intermediate. Bathorhodopsin is transformed in several steps into metarhodopsin II which couples with the G-protein and triggers the visual cascade. Rhodopsin is the first GPCR of which the X-ray structure has been solved. This structure is a first step for understanding the visual process at the molecular level. However, the 2.8 Å resolution is not sufficient for a detailed analysis of the chromophore and its interaction with the protein environment. Fine points of the chromophore geometry, which are essential for the selectivity and reactivity of the receptor and the subsequent interconversions, remain in doubt. Subject of the proposal is the calculation of realistic models of rhodopsin and of bathorhodopsin based on the experimental X-ray structure. We will use rigorous quantum-chemistry for the chromophore, density functional-based tight-binding (DFTB) for the chromophore including the binding pocket, and combined quantum mechanical/molecular mechanics for the whole protein. The focus, for rhodopsin, will be on the tight fit between the chromophore and protein, which stabilizes the ground state and sets it up for photo-isomerization. For bathorhodopsin, we will concentrate on the steric non-fit of the chromophore after photoexcitation, how its enforced geometry affects the binding pocket and prepares the whole protein on its path towards G-protein activation.

视紫红质是脊椎动物眼睛中用于昏暗视觉的光感受器，是一种所谓的g蛋白偶联受体或GPCR。视紫红质的视觉级联反应的首要步骤是视紫红质的发色团——视网膜的C11=C12双键由顺式异构化到反式异构化，形成视紫红质的中间体。深视紫红质经过几个步骤转化为后视紫红质II，后者与g蛋白偶联并触发视觉级联。视紫红质是第一个x射线结构已被解决的GPCR。这种结构是在分子水平上理解视觉过程的第一步。然而，2.8 Å分辨率不足以详细分析发色团及其与蛋白质环境的相互作用。对受体的选择性和反应性以及随后的相互转换至关重要的生色团几何结构的精细点仍然存在疑问。本文的主题是基于实验x射线结构计算视紫红质和深紫红质的真实模型。我们将对发色团使用严格的量子化学，对包括结合袋在内的发色团使用基于密度函数的紧密结合（DFTB），对整个蛋白质使用量子力学/分子力学相结合的方法。对于视紫红质来说，重点将放在发色团和蛋白质之间的紧密配合上，这将稳定基态并为光异构化做好准备。对于深紫红质，我们将专注于光激发后发色团的立体不配合，其强制几何形状如何影响结合袋并准备整个蛋白质走向g蛋白激活的路径。