Atomic-level, large-scale structure prediction of G protein-coupled receptors

G蛋白偶联受体的原子水平大规模结构预测

基本信息

批准号：
8233525
负责人：
Yang Zhang
金额：
$ 31.59万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233525
关键词：
Acetylcholine Adrenergic Agents Adrenergic Receptor Algorithms Amino Acid Sequence Architecture Bacteriorhodopsins Benchmarking Biological Process Biology Cattle Cell Surface Receptors Chemicals Collaborations Communities Computational algorithm Computers Computing Methodologies Data Databases Development Disease Dopamine Drug Delivery Systems Drug Design Eukaryotic Cell Family Feedback G-Protein-Coupled Receptors GTP-Binding Proteins Generations Goals Histamine Human Integral Membrane Protein Knowledge Length Ligand Binding Ligands Literature Medical Membrane Proteins Methodology Methods Modeling Molecular Muscarinic Acetylcholine Receptor Muscarinics Mutagenesis Pharmaceutical Preparations Pharmacologic Substance Physics Physiological Plant Roots Preclinical Drug Evaluation Procedures Protein Family Proteins Proteome Proteomics Public Health Relative (related person)Resolution Rhodopsin Role Scientist Screening procedure Side Signal Transduction Site-Directed Mutagenesis Speed Staging Structure Testing Validation Variant Vertebral column Weight adrenergic base chemokine database structure design drug discovery extracellular fighting improved knowledge base member models and simulation protein activation protein structure receptor repository research study restraint success three dimensional structure user-friendly virtual web site

项目摘要

Description/Project Summary G protein-coupled receptors (GPCRs) are the largest family of integral membrane proteins that occur in nearly every eukaryotic cell to transduce an extracellular signal (ligand binding) into an intracellular signal (G protein activation). This essential physiological role makes them the most important pharmaceutical targets which comprise approximately half of today's modern medicinal drugs. Clearly, 3D-structures of GPCRs would provide essential atomic-level information for elucidating the molecular organization and for efficient virtual screening of drug databases. However, except for the recently solved human beta2-andrenergic receptor, it has not yet been possible to obtain experimental structural information for other human GPCRs. Building on the recent success of the threading assemble refinement (TASSER) algorithm for reduced-level GPCR modeling, this proposal seeks to develop new computational methodologies for the generation of experiment- validated, atomic-level GPCR models. The focus will be on five pharmaceutically important families including Adrenergic, Chemokine, Dopamine, Histamine, and Muscarinic acetylcholine. Specific aims of the project are: (1) Development and benchmarking of a new GPCR-TASSER algorithm for atomic-level GPCR protein structure modeling. (2) Development and optimization of composite atomic and reduced GPCR potentials. (3) Dissemination of GPCR-TASSER algorithm for public use and examination. (4) Application of GPCR-TASSER to the pharmaceutically important GPCRs. (5) Validation and refinement of the GPCR models with experiment collaborators. The long-term goals are (a) to develop a set of computer algorithms for automated and atomic- level GPCR structure prediction (b) to extend the methodology to proteomic-scale structure modeling for all GPCRs in UniProt database (c) to construct a central repository for publicly-accessible GPCR algorithms and structure databases which are designed to eventually alleviate the urgent need in biology and medical communities for the detailed atomic GPCR structures.

描述/项目摘要 G蛋白偶联受体（GPCR）是最大的整体膜蛋白家族，发生在几乎每个真核细胞中，都会将细胞外信号（配体结合）转导细胞内信号（G蛋白激活）。这种重要的生理角色使他们最大重要的药物靶标，其中约占当今现代药物的一半毒品。显然，GPCR的3D结构将为基本的原子级信息提供阐明分子组织并有效地筛选药物数据库。然而，除了最近解决的人beta2 andrenergic受体外，尚无可能获得其他人GPCR的实验结构信息。建立在最近成功的基础上螺纹组装细化（Tasser）算法用于降低级别的GPCR建模，此提案旨在开发新的计算方法，以生成实验 - 经过验证的原子级GPCR模型。重点将放在五个重要重要家庭包括肾上腺素能，趋化因子，多巴胺，组胺和毒蕈碱乙酰胆碱。该项目的具体目的是：（1）新GPCR-Tasser的开发和基准测试原子级GPCR蛋白结构建模的算法。（2）开发和优化复合原子和降低的GPCR电位。（3）GPCR-TASSER算法的传播公众使用和检查。（4）将GPCR-Tasser应用于药品很重要 GPCR。（5）通过实验合作者对GPCR模型的验证和完善。长期目标是（a）为自动化和原子的一组计算机算法开发级别GPCR结构预测（B）将方法扩展到蛋白质组学结构建模对于Uniprot数据库（C）中的所有GPCR 算法和结构数据库旨在最终减轻迫切需求详细原子GPCR结构的生物学和医学界。