Understanding Molecular Recognition at the Rhodopsin/Transducin Interface

了解视紫红质/转导蛋白界面的分子识别

• 批准号: 7556771
• 负责人: Christina Marie Taylor
• 金额: $ 2.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7556771
• 关键词: Binding; Binding Proteins; C-terminal; Chemistry; Computational Technique; Computer Simulation; Computer software; Computing Methodologies; Data; Disease; Docking; Drug Delivery Systems; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Lead; Learning; Libraries; Ligands; Light; Literature; Marketing; Measurement; Membrane; Methodology; Methods; Modeling; Molecular; Molecular Conformation; Molecular Models; Mutation; Night Blindness; Pathologic Processes; Peptides; Pharmaceutical Preparations; Play; Procedures; Process; Proteins; Protons; Reaction; Research; Retinal; Retinal Diseases; Rhodopsin; Roentgen Rays; Role; Signal Transduction; Signaling Protein; Spin Labels; Structure; Techniques; Testing; Therapeutic; Transducin; Vision; Work; analog; base; combinatorial chemistry; design; disease-causing mutation; drug discovery; extracellular; high throughput screening; inhibitor/antagonist; molecular modeling; molecular recognition; mutant; peptidomimetics; protein protein interaction; prototype; small molecule; small molecule libraries

DESCRIPTION (provided by applicant): G-protein coupled receptors (GPCRs) are involved in many pathological processes and implicated in many diseases; over 50% of the drugs target GPCRs. Rhodopsin, the retinal GPCR, is used as the prototypical GPCR because it is the only GPCR for which an X-ray structure exists. Following light exposure, rhodopsin changes conformation (R->R*), allowing its G-protein, transducin, to bind. The interaction of the transducin C-terminal region Gtalpha(340-350) with the intracellular loops of rhodopsin is critical for GDP/GTP exchange and subsequent signal amplification in the vision cascade. Some congenital mutations in rhodopsin cause rhodopsin to stay in the R* state, leading to constitutive signal amplification. The goal of my research is to learn about the molecular recognition between rhodopsin and transducin and develop a molecular therapeutic to block this interaction. Using both experimental and computational techniques, I will determine the binding mode and residue-residue interactions of Gtalpha(340-350) peptides and peptidomimetics with R*. I will use parallel techniques to derive a small molecule to inhibit the rhodopsin/transducin interaction. First, I will use modeling software and computational high-throughput screening to design an inhibitor. Secondly, I will explore the use of high-efficiency reactions to generate peptidomimetic compounds using rhodopsin to template the reaction. Statement of Relevance: Despite a large number of drugs on the market targeting G-protein coupled receptors (GPCRs), very little is known about how GPCRs interact with other proteins and signal downstream processes. Using rhodopsin, the prototypical GPCR involved in vision, I will determine how rhodopsin and transducin (rhodopsin's G-protein) interact using experimental and computational methods, and I will design and test a small molecule to block this interaction. This work will provide general information about how GPCRs interact with G-proteins and potentially lead to a small molecule therapeutic for some congenital retinal diseases.

描述（申请人提供）：G蛋白偶联受体（GPCR）参与许多病理过程并与许多疾病有关；超过 50% 的药物以 GPCR 为靶点。视紫红质（视网膜 GPCR）被用作原型 GPCR，因为它是唯一存在 X 射线结构的 GPCR。光照后，视紫红质改变构象（R->R*），使其 G 蛋白（转导蛋白）结合。转导蛋白 C 末端区域 Gtalpha(340-350) 与视紫质细胞内环的相互作用对于视觉级联中的 GDP/GTP 交换和随后的信号放大至关重要。视紫红质的一些先天性突变会导致视紫红质保持在 R* 状态，从而导致组成型信号放大。我的研究目标是了解视紫红质和转导蛋白之间的分子识别，并开发一种分子疗法来阻止这种相互作用。使用实验和计算技术，我将确定 Gtalpha(340-350) 肽和肽模拟物与 R* 的结合模式和残基-残基相互作用。我将使用并行技术衍生出一种小分子来抑制视紫红质/转导蛋白相互作用。首先，我将使用建模软件和计算高通量筛选来设计抑制剂。其次，我将探索利用视紫红质作为反应模板，利用高效反应来生成拟肽化合物。相关性声明：尽管市场上有大量针对 G 蛋白偶联受体 (GPCR) 的药物，但人们对 GPCR 如何与其他蛋白质相互作用以及向下游过程发出信号知之甚少。使用视紫红质（参与视觉的典型 GPCR），我将使用实验和计算方法确定视紫红质和转导蛋白（视紫红质的 G 蛋白）如何相互作用，并且我将设计和测试一种小分子来阻止这种相互作用。这项工作将提供有关 GPCR 如何与 G 蛋白相互作用的一般信息，并有可能开发出治疗某些先天性视网膜疾病的小分子疗法。