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Structural Dynamics of Retinal Binding and Release

视网膜结合和释放的结构动力学

基本信息

批准号：
8403607
负责人：
David L Farrens
金额：
$ 36.29万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403607
关键词：
Address Affect Affinity Apoptosis Arrestins Attenuated Binding Biological Assay Complex Data Disease Event Family Funding G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Goals Health Human Human Genome Hydrolysis Kinetics Leber&apos s disease Life Light Methods Modeling Molecular Monitor Mutagenesis Mutation Night Blindness Nonexudative age-related macular degeneration Opsin Pharmaceutical Preparations Pharmacologic Substance Play Process Proteins Research Resolution Retinal Retinal Cone Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Role Scheme Schiff Bases Signal Transduction Site Structure System Testing Time Vertebrate Photoreceptors Vision Vision research Visual Visual Signal Transduction Pathway Work adduct attenuation base chromophore design follow-up insight novel preference prevent protein structure receptor receptor coupling research study theories uptake

项目摘要

PROJECT SUMMARY The long-term goal of our research is to understand the molecular mechanisms through which G-protein coupled receptors (GPCRs) are activated and attenuated. These receptors represent the largest family in the human genome, and they are the target of most pharmaceutical drugs. We focus our studies primarily on the GPCR rhodopsin and its affiliate proteins. Although crystal structures of key proteins involved in visual signaling are now known, most of the critical structural changes these proteins undergo during their activation and attenuation remain largely a matter of speculation. In particular, we lack even rudimentary information about the dynamic events involved in attenuating rhodopsin signaling, namely, the mechanisms through which retinal is released from the opsin-binding pocket, and how retinal binding and release affects arrestin binding and release. Understanding these processes is of fundamental importance for vision research - the stability of the retinal linkage varies widely among different opsins and is a factor in some visual disease states. Furthermore, although much is known about the mechanism and kinetics of arrestin binding to rhodopsin, little is known about what makes arrestin release after binding, and how this release is related to the status of the retinal chromophore. In Aim I of this proposal we will determine how rhodopsin controls the hydrolysis of its retinal Schiff base linkage. In Aim II we will examine how retinal uptake and release occurs in rhodopsin, using the recent structure of opsin to guide our studies. Finally, in Aim III, we will use our novel methods to follow up on a discovery we made during the last funding period - that arrestin can bind to MIII rhodopsin, thus trapping and preventing retinal release. Understanding how arrestin regulates retinal release is fundamentally important to health, as arrestin may serve to limit the release of free retinal under bright light conditions, and thus help limit the formation of oxidative retinal adducts that can contribute to diseases like atrophic age-related macular degeneration (AMD). Similarly, understanding what makes arrestin "let go" after binding rhodopsin is also crucial - stable rhodopsin-arrestin complexes have been suggested to be a contributing factor in apoptosis and autosomal dominant retinitis pigmentosa (ADRP).

项目总结