Mechanisms of Allostery and Molecular Recognition in the Small Multidrug Resistan

描述（由申请人提供）：本提案的目标是表征小多药耐药（SMR）蛋白家族的变构和药物识别机制。对抗生素的多重耐药（MDR）是细菌同时对多种化学上不同的分子产生耐药性的能力。虽然已经成功开发和改良了几种具有不同化学支架的新抗生素，但耐多药仍然是医院和诊所普遍存在的问题。我们将揭示变构控制机制和分子相互作用在原子水平上，使SMR蛋白识别各种各样的药物。这些分子马达需要能量依赖的构象转变和蛋白质-蛋白质大分子组装来实现功能。我们的高分辨率结构生物学方法将采用核磁共振波谱来揭示分子水平上的细节。虽然生物化学和生物物理学研究为这项研究奠定了基础，但这些蛋白质识别药物、被激活并随后赋予耐药性的分子机制尚不清楚。我们的研究将为深入了解这一重大的人类健康问题提供结构动力学-功能相关性，这样做将从SMR家族的角度揭示耐多药现象的分子图谱，该图谱可应用于其他家族，以便更好地了解临床耐药性。

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.