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Conformational dynamics of adhesive bonds

粘合键的构象动力学

基本信息

批准号：
9257278
负责人：
EVGENI Veniaminovic SOKURENKO
金额：
$ 59.65万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-10 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9257278
关键词：
Address Adhesions Adhesives Animal Model Antibiotic Resistance Antibodies Automobile Driving Bacteria Bacterial Adhesins Bacterial Adhesion Bacterial Infections Behavior Binding Biological Assay Blood Cells Cadherins Capsid Proteins Categories Cell Adhesion Cell Surface Receptors Cell-Matrix Junction Cells Characteristics Data Disease Distal Effectiveness Enzymes Epithelial Escherichia coli Escherichia coli Adhesins Eukaryotic Cell Exhibits Future Goals Immune Infection Infection prevention Infective cystitis Inflammation Inflammatory Integrins Kinetics Ligand Binding Ligands Link Liquid substance Malignant Neoplasms Mannose Measures Mechanics Mediating Methods Microbial Biofilms Modeling Molecular Molecular Conformation Movement Mus Nuclear Magnetic Resonance Pharmaceutical Preparations Physiological Physiology Play Process Protein Conformation Proteins Receptor Cell Regulation Role Salvelinus Site Spectrum Analysis Structure Surface Surface Plasmon Resonance Testing Therapeutic Intervention Tissues Urinary tract infection Uropathogenic E. coli Vaccines Virus Work X-Ray Crystallography bacterial resistance design experimental study in vivo inhibiting antibody inhibitor/antagonist mechanical force molecular dynamics novel novel strategies prevent prototype public health relevance receptor receptor binding response simulation single molecule targeted treatment urovirulent isolates

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY Adhesive receptors are a class of cell surface receptor that binds to surface-bound ligands to mediate cell adhesion to other cells or tissues. Adhesive receptors play a critical role in physiology and disease, and so are common targets for therapeutic interventions for a wide range of diseases. The goal of this project is to understand the dynamic conformational changes that allow adhesive receptors to mediate strong cell adhesion in vivo, in order to develop better methods for their inhibition. This project focuses on the bacterial adhesin FimH, which is implicated in infection of the urinary tract by Escherichia coli. This should provide alternative methods to treat or prevent infections involving antibiotic-resistant bacteria. The novelty of this project is that it addresses how mechanical force regulates the dynamic conformational changes of adhesive receptors. This project tests the hypothesis that FimH utilizes tensile mechanical force transmitted by the bound ligand to close the binding pocket tightly around the ligand, allowing extremely tight binding in the presence of mechanical force. This project will test the hypothesis that a novel type of 'parasteric' inhibitor can directly open the FimH binding pocket even in the presence of mechanical force. The project will also test the hypothesis that FimH will be more effectively inhibited in physiological conditions by parasteric inhibitors than by conventional orthosteric or allosteric inhibitors. The following approaches will be used to obtain these goals. 1) The binding kinetics of FimH will be measured, both with and without mechanical force, in the presence of parasteric, orthosteric and allosteric inhibitory antibodies. 2) The structure and conformational dynamics of FimH will be determined in the presence of three types of antibodies using NMR, X-ray crystallography and atomistic structural simulations. 3) The effectiveness of the three types of antibodies will be compared, for preventing bacterial adhesion to uroepithelial cells, as well a urinary tract infections in mice. This work will provide rationale for FimH vaccine and inhibitor designs. This work will also provide rationale for developing inhibitors for many other adhesive receptors, which are attractive targets for therapeutic interventions for thrombotic and inflammatory diseases, cancer, and many other diseases.