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Structure, Dynamics and Activation Mechanisms of Chemokine Receptors

趋化因子受体的结构、动力学和激活机制

基本信息

批准号：
8695411
负责人：
RUBEN ABAGYAN
金额：
$ 89.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8695411
关键词：
Acquired Immunodeficiency Syndrome Affinity Agonist Arrestins Asthma Binding Biological Process Biology Cells Chemokine (C-C Motif) Receptor 5 Cocrystallography Cognition Collaborations Complement Complex Computer Analysis Computer Simulation Coupling Crystallization Crystallography Data Deposition Development Disease Docking Drug Targeting Electron Spin Resonance Spectroscopy Emotions Endocrine system Ensure Esthesia Event Family G-Protein-Coupled Receptors GTP-Binding Proteins Glycoproteins Goals HIV HIV Envelope Protein gp120 Heart Diseases Human Immune system Immunologic Surveillance Infection Inflammatory Insecta Internet Intracellular Signaling Proteins Ligand Binding Ligands Light Malignant Neoplasms Mammalian Cell Maps Mass Spectrum Analysis Membrane Methodology Methods Modeling Modification Multiple Sclerosis Mutagenesis Mutation Output Pathology Pharmaceutical Preparations Physiological Play Principal Investigator Production Property Protein Structure Initiative Proteins Protocols documentation Receptor Activation Regulation Resolution Rheumatoid Arthritis Role Signal Transduction Signaling Protein Site Solvents Source Spin Labels Stimulus Structural Models Structure Surface Synchrotrons Technology Work base chemokine chemokine receptor data integration design design and construction drug discovery human disease improved innovation insight intercellular communication interest knowledge base leukocyte activation member migration mutant neurotransmission new technology overexpression public health relevance receptor receptor binding receptor expression receptor function restraint small molecule structural genomics

项目摘要

DESCRIPTION (provided by applicant): G protein coupled receptors (GPCRs) represent the largest protein superfamily in humans, with nearly 1000 members. They are seven transmembrane receptors that coordinate intercellular communication via the transduction of a wide range of stimuli involved in sensation, neurotransmission, development, emotion, cognition, and function in the CNS, endocrine and immune systems. Chemokine receptors are an important class of GPCRs that are best known for their pivotal role in immune surveillance, where they control the migration and activation of leukocytes in an effort to detect and resolve physiological abnormalities such as cancer and infection. However, inappropriate expression or regulation of these receptors is associated with an extraordinary number of pathologies including inflammatory diseases, cancer and AIDS; thus there is significant interest in developing small molecule receptor antagonists that block the function of specific chemokine receptors. Until recently, GPCRs had eluded structure determination due to challenges in receptor expression and crystallization. However, new technologies have emerged which has made the viability of determining GPCR structures indisputable. To this end, our primary goal is to obtain structural information on chemokine receptors and receptor complexes that can aid drug discovery efforts aimed at improving affinity, efficacy, and selectivity. Accordingly, in collaboration with the PSI network, we will apply novel technologies for the expression, purification and crystallization of GPCRs from the chemokine receptor family, with the goal of determining at least two different receptor structures and multiple co-complexes by the five-year endpoint. To maximize the capabilities of the PSI centers in generating purified protein, and to acquire insights into the dynamic aspects of receptor function, the crystallographic work will be complemented with biophysical studies. Radiolytic footprinting will be developed and applied to map the binding interfaces between chemokines and receptors and to determine information on activation mechanisms. The interaction of pathogenic proteins with chemokine receptors will also be investigated, specifically, the CCR5 receptor with the HIV glycoprotein gp120, and the DARC receptor with the malarial docking protein, DBP. Site Directed Spin Labeling with Electron Paramagnetic Resonance (SDSL-EPR) will be used to characterize the conformational changes associated with ligand binding. All of these studies will be augmented with computational modeling methods in order to rationally guide the experimental construct design and to interpret the biophysical data in a 3D context.

描述(申请人提供)：G蛋白偶联受体(GPCRs)是人类最大的蛋白质超家族，有近1000个成员。它们是七种跨膜受体，通过转导一系列刺激来协调细胞间的交流，这些刺激涉及中枢神经系统、内分泌和免疫系统中的感觉、神经传递、发育、情感、认知和功能。趋化因子受体是一类重要的GPCRs，以其在免疫监测中的关键作用而闻名，在免疫监测中，它们控制白细胞的迁移和激活，以努力检测和解决诸如癌症和感染等生理异常。然而，这些受体的不适当表达或调节与许多病理疾病有关，包括炎症性疾病、癌症和艾滋病；因此，开发小分子受体拮抗剂来阻断特定趋化因子受体的功能受到了极大的关注。直到最近，由于受体表达和结晶方面的挑战，GPCRs一直难以确定结构。然而，新技术的出现使得确定GPCR结构的可行性是毋庸置疑的。为此，我们的主要目标是获得趋化因子受体和受体复合体的结构信息，以帮助旨在提高亲和力、有效性和选择性的药物开发工作。因此，我们将与防扩散安全倡议网络合作，来自趋化因子受体家族的GPCRs的表达、纯化和结晶的新技术，目标是在五年终点之前确定至少两种不同的受体结构和多个共同复合体。为了最大限度地发挥PSI中心产生纯化蛋白的能力，并深入了解受体功能的动态方面，结晶学工作将与生物物理研究相辅相成。辐射分解足迹将被开发和应用于绘制趋化因子和受体之间的结合界面，并确定激活机制的信息。致病蛋白与趋化因子受体的相互作用也将被研究，特别是CCR5受体与HIV糖蛋白gp120，DARC受体与疟疾对接蛋白DBP。电子顺磁共振定位自旋标记(SDSL-EPR)将用于表征与配体结合相关的构象变化。所有这些研究都将用计算建模方法加以补充，以便合理地指导实验结构设计并在三维环境中解释生物物理数据。