Mechanisms of Allostery and Molecular Recognition in the Small Multidrug Resistan

小型多药耐药性的变构和分子识别机制

• 批准号: 8761801
• 负责人: Nathaniel J. Traaseth
• 金额: $ 38.84万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761801
• 关键词: Abbreviations; Active Biological Transport; Address; Animals; Antibiotic Resistance; Antibiotics; Architecture; Bacteria; Binding; Biochemical; Biocide; Cations; Cells; Chemicals; Clinical; Clinics and Hospitals; Coupled; Coupling; Drug Efflux; Drug toxicity; Electronics; Environment; Erythromycin; Exhibits; Family; Foundations; Goals; Health; Homologous Gene; Human; Hybrids; Infection; Ions; Ligands; Lipids; Local Anti-Infective Agents; Magic; Membrane; Membrane Lipids; Modeling; Molecular; Molecular Conformation; Molecular Motors; Molecular Structure; Multi-Drug Resistance; Mutation; NMR Spectroscopy; Nature; Organism; P-Glycoproteins; Pattern; Pharmaceutical Preparations; Protein Family; Proteins; Proton-Motive Force; Research; Research Project Grants; Resistance; Resistance profile; Resolution; Role; Shapes; Side; Site; Solutions; Specificity; Structure; Testing; Transport Process; antiport; base; combat; conformational conversion; design; efflux pump; flexibility; inhibitor/antagonist; insight; macromolecular assembly; molecular recognition; multi drug transporter; mutant; novel therapeutics; pathogen; public health relevance; research study; resistance mechanism; scaffold; solid state nuclear magnetic resonance; structural biology; trait

DESCRIPTION (provided by applicant): The goal of this proposal is to characterize the mechanisms of allostery and drug recognition within the small multidrug resistance (SMR) protein family. Multidrug resistance (MDR) to antibiotics is the ability of bacteria to confer simultaneous resistance to a wide variety of chemically distinct molecules. While several new antibiotics exhibiting different chemical scaffolds have been successfully developed and modified, MDR remains a pervasive problem in hospitals and clinics. We will reveal the allosteric control mechanism and molecular interactions at the atomic level that enable SMR proteins to recognize a wide variety of drugs. These molecular motors require energy dependent conformational transitions and protein-protein macromolecular assemblies to carry out function. Our high-resolution structural biology approach will employ NMR spectroscopy to reveal the details at the molecular level. While biochemical and biophysical studies have laid the foundation for this research, the molecular mechanism by which these proteins recognize drugs, become activated, and subsequently confer resistance is unknown. Our studies will provide a structural dynamics-function correlation for providing insight into this significant human health problem, and in doing so will reveal a molecular picture of the MDR phenomenon from the standpoint of the SMR family that can be applied to other families in order to better understand clinical resistance.

描述(由申请人提供)：本提案的目标是描述小分子多药耐药(SMR)蛋白家族中变构和药物识别的机制。对抗生素的多药耐药性(MDR)是指细菌对各种化学上不同的分子同时产生耐药性的能力。虽然已经成功地开发和修改了几种展示不同化学支架的新抗生素，但MDR仍然是医院和诊所普遍存在的问题。我们将揭示使SMR蛋白能够识别多种药物的变构控制机制和原子水平上的分子相互作用。这些分子马达需要能量依赖的构象转变和蛋白质-蛋白质大分子组装才能发挥作用。我们的高分辨率结构生物学方法将使用核磁共振波谱在分子水平上揭示细节。虽然生化和生物物理研究已经为这项研究奠定了基础，但这些蛋白质识别药物、激活并随后产生耐药性的分子机制尚不清楚。我们的研究将提供结构动力学-功能相关性，以深入了解这一重大的人类健康问题，并通过这样做将从SMR家族的角度揭示MDR现象的分子图景，可以应用于其他家庭，以便更好地了解临床耐药。