CRYSTALLOGRAPHIC STUDIES OF ANTIBIOTIC RESISTANCE PROTEINS AND SIGNAL TRANSDUCTI

抗生素耐药蛋白和信号转导的晶体学研究

• 批准号: 8170149
• 负责人: FOCCO VAN DEN AKKER
• 金额: $ 0.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170149
• 关键词: Antibiotic Resistance; Antibiotics; Bacterial Infections; Binding; Bone Growth; Carbapenems; Clinical Trials; Coiled-Coil Domain; Collaborations; Complex; Computer Retrieval of Information on Scientific Projects Database; Cyclic Nucleotides; Data Set; Development; Disease Outbreaks; Funding; Grant; Guanylate Cyclase; Human; Institution; Ion Channel; Klebsiella pneumonia bacterium; L-Selenomethionine; Lactamase; Lead; Link; Methodist Church; Molecular; New York; Pharmacologic Substance; Physiological Processes; Research; Research Personnel; Resolution; Resort; Resources; Roentgen Rays; Signal Pathway; Signal Transduction; Signaling Protein; Source; Structure; United States National Institutes of Health; Universities; bacterial resistance; beta-lactamase PSE-2; blood pressure regulation; clinically relevant; design; inhibitor/antagonist; insight; novel; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of antibiotic resistance to bacterial infections is a serious human threat in large part due to bacterial b-lactamases. Inhibition of these b-lactamases is therefore a key pharmaceutical approach. Our lab focuses on delineating the molecular inhibition mechanism of clinically available inhibitors, additional potent inhibitors that are in, or close to, clinical trials, and our own designed inhibitors. The inhibition mechanism is complex involving a large number of covalent intermediates that we study using a novel X-ray and Raman crystallographic approach. High resolution crystallographic studies are proposed for inhibitor complexes for a variety of different clinically relevant b-lactamases classes including KPC-2, recently linked to an K. pneumoniae outbreak in New York, SHV-1, and OXA-1, OXA-10, and OXA-24/40. Both OXA24/40 and KPC-2 are a major threat to carbapenems, a last resort antibiotic. Our inhibitors are developed in collaboration with Dr. Buynak (Southern Methodist University) and are designed to form a stable inhibitory intermediate, either by forming a trans-enamine or bicyclic aromatic ring intermediate. In addition, we are embarking on using fragment-mixture soaked b-lactamase crystals as a tool for finding new lead compounds. In addition, our lab focuses on structural studies of cyclic nucleotide signaling. We have recently crystallized the coiled-coil domain of a guanylyl cyclase involved in blood pressure regulation. Crystals diffract to 2¿ and we plan on collecting a SeMet MAD dataset. Finally, we have crystallized several cyclic nucleotide binding domains of ion channels of which we determined the structure of one, and have diffracting crystals for two others. The latter project is aimed to providing structural insights into cyclic nucleotide signaling pathways involving in blood pressure regulation, bone growth and other important physiological processes.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 在很大程度上，由于细菌B-乳糖苷酶，对细菌感染的抗生素耐药性的发展是严重的人类威胁。因此，抑制这些B-内乳酶是一种关键的药物方法。我们的实验室重点是描述临床上可用抑制剂的分子抑制机制，临床试验或接近临床试验的其他潜在抑制剂以及我们自己设计的抑制剂。抑制作用机制是复杂的，涉及我们使用新型X射线和拉曼晶体学方法研究的大量共价中间体。提出了针对各种不同临床相关的B-内乳酶类别的抑制剂复合物的高分辨率晶体学研究，这些类别包括KPC-2，最近与纽约肺炎的K. o. tneumoniae爆发有关，SHV-1和OXA-1，OXA-1，OXA-100和OXA-24/40。 OXA24/40和KPC-2都是对碳青霉烯的主要威胁，这是一种抗生素。我们的抑制剂是与Buynak博士（南方卫理公会大学）合作开发的，旨在形成稳定的抑制性中间体，通过形成跨 - 氨基胺或生物芳香环中间体。此外，我们正在使用片段混合浸泡的B-内酰胺酶晶体作为寻找新铅化合物的工具。此外，我们的实验室重点介绍了循环核丁基信号传导的结构研究。我们最近有晶体衍射为2，我们计划收集一个SEMET MAD数据集。最后，我们已经结晶了几个循环核苷酸结合结构域的离子通道的结构，并确定了一个循环核苷酸的结构，并具有另外两个的衍射晶体。后一个项目旨在为涉及血压调节，骨骼生长和其他重要物理过程的环状核苷酸信号通路提供结构见解。