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Structural Basis of chemokine CXCL1 recognition with CXCR2 receptor

趋化因子 CXCL1 与 CXCR2 受体识别的结构基础

基本信息

批准号：
10488181
负责人：
Krishna Rajarathnam
金额：
$ 20万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-13 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10488181
关键词：
Acute Disease Address Affinity Automobile Driving Binding Binding Proteins Binding Sites Brain CCR5 gene CCR6 gene CXCL1 gene CXCR4 gene Cellular Assay Characteristics Charge Chronic Disease Clinical Communicable Diseases Complex Coupled Cryoelectron Microscopy Crystallization Data Disease Docking Functional disorder G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Grant Heart Human Hybrids Hydrophobicity IL8 gene IL8RB gene Infection Inflammatory Injury Interleukin-8B Receptor Knowledge Lung Measurement Measures Mediating Methods Molecular Molecular Conformation Motion N-terminal NMR Spectroscopy Nature Neutrophil Infiltration Nuclear Magnetic Resonance Organ Outcome Play Process Proteins Receptor Activation Research Proposals Role Sequence Analysis Signal Transduction Site Specificity Structural Models Structure Testing Therapeutic Tissues Variant base beta-arrestin chemokine chemokine receptor design dimer drug development extracellular flexibility insight molecular dynamics monomer mutant neutrophil public health relevance receptor response spatiotemporal tool trafficking

项目摘要

Chemokine CXCL1, and its receptor CXCR2, a class-A G protein-coupled receptor (GPCR), play a crucial role in directing blood neutrophils to sites of infection and injury. A dysregulation in CXCR2 activation results in host tissue damage and disease. CXCL1 binds CXCR2 at two distinct sites: N- terminal domain (Site-I, unique to chemokines) and a groove defined by the receptor extracellular loops/transmembrane helices (Site-II, shared with all class A receptors). The molecular basis by which chemokine binding two distinct sites determine CXCR2 activation is not known. Structures and sequence analyses reveal that chemokine and receptor residues that mediate binding are either unstructured or conformationally dynamic. We propose that CXCL1 binding at Site-I of CXCR2, the initial obligatory step, triggers structural and dynamic changes that are essential for Site-II interactions. We will test our hypothesis using a hybrid strategy that combines nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations. We will determine the structure and characterize the role of conformational dynamics of Site-I CXCL1-CXCR2 N-terminal domain complex using NMR spectroscopy (Aim 1). We will generate a structural model of CXCL1 bound to CXCR2 at the N-terminal domain by merging Site-I NMR structure and previously determined CXCR2 structure, and use extended MD simulations to describe how CXCL1 bound at Site-I engages the receptor at Site-II (Aim 2). We will characterize how CXCL1 Site-I and Site-II residues identified from Aims 1 and 2 mediate CXCR2 activation using cellular assays (Aim 3). These studies will provide critical insights into the molecular mechanisms underlying CXCR2 activation and will advance designing therapeutics that disrupt CXCR2 activation and alleviate disease.

趋化因子CXCL 1及其受体CXCR 2，一种A类G蛋白偶联受体（GPCR），在细胞内发挥作用。在将血液中性粒细胞引导至感染和损伤部位方面起着至关重要的作用。CXCR 2失调激活导致宿主组织损伤和疾病。CXCL 1在两个不同的位点结合CXCR 2：末端结构域（位点-I，趋化因子特有）和由受体胞外限定的沟环/跨膜螺旋（位点II，与所有A类受体共享）。分子基础，哪种趋化因子结合两个不同的位点决定CXCR 2的活化尚不清楚。结构和序列分析表明，趋化因子和受体残基介导的结合，非结构化或构象动态。我们认为CXCL 1与CXCR 2的I位点结合，最初的强制性步骤，触发对站点II至关重要的结构和动态变化交互.我们将使用一种混合策略来测试我们的假设，共振（NMR）光谱和分子动力学（MD）模拟。康贝特人将以 CXCL 1-CXCR 2 N-末端I位点的结构和构象动力学特征域复合物使用NMR光谱（目的1）。我们将生成CXCL 1的结构模型通过合并位点-I NMR结构和先前的确定的CXCR 2结构，并使用扩展的MD模拟来描述CXCL 1如何在位点-I与位点-II处的受体接合（目的2）。我们将描述CXCL 1站点I和站点II 从目的1和2鉴定的残基使用细胞测定介导CXCR 2活化（目的3）。这些这些研究将为CXCR 2激活的分子机制提供重要的见解，将促进设计破坏CXCR 2激活和减轻疾病的治疗方法。