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: 7954491
• 负责人: FOCCO VAN DEN AKKER
• 金额: $ 0.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954491
• 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; structural biology; synchrotron radiation; 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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细菌感染的抗生素耐药性的产生是对人类的严重威胁，这在很大程度上是由于细菌的β-内酰胺酶造成的。因此，抑制这些β-内酰胺酶是一种关键的制药方法。我们的实验室专注于描述临床可用抑制剂、正在进行或接近临床试验的额外有效抑制剂以及我们自己设计的抑制剂的分子抑制机制。其缓蚀机理是复杂的，涉及大量的共价中间体，我们用一种新的X射线和拉曼结晶学方法对其进行了研究。高分辨率的结晶学研究被提议用于各种不同临床相关的β-内酰胺酶的抑制剂复合体，包括最近与纽约肺炎克雷伯菌暴发有关的KPC-2，SHV-1，以及OXA-1，OXA-10和OXA-24/40。OXA24/40和KPC-2都是对碳青霉烯类抗生素的主要威胁，碳青霉烯是一种最后的抗生素。我们的抑制剂是与Buynak博士(南方卫理公会大学)合作开发的，旨在通过形成反式烯胺或双环芳环中间体来形成稳定的抑制中间体。此外，我们正在着手使用碎片混合物浸泡的β-内酰胺酶晶体作为寻找新的先导化合物的工具。此外，我们的实验室专注于环核苷酸信号的结构研究。我们最近结晶了参与血压调节的鸟苷酸环化酶的卷曲卷曲结构域。晶体衍射率为2？，我们计划收集一个Semet MAD数据集。最后，我们结晶了几个离子通道的环核苷酸结合域，我们确定了其中一个的结构，并得到了另外两个的衍射晶。后一个项目的目的是提供对环核苷酸信号通路的结构洞察，这些信号通路涉及血压调节、骨生长和其他重要的生理过程。