CRYSTALLOGRAPHIC STUDIES OF ANTIBIOTIC RESISTANCE PROTEINS AND SIGNAL TRANSDUCTI

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 对细菌感染的抗生素耐药性的发展是严重的人类威胁，这在很大程度上是由于细菌b-内酰胺酶。因此，抑制这些β-内酰胺酶是关键的药学方法。我们的实验室专注于描绘临床可用抑制剂的分子抑制机制，在临床试验中或接近临床试验的其他有效抑制剂，以及我们自己设计的抑制剂。的抑制机制是复杂的，涉及大量的共价中间体，我们研究使用一种新的X-射线和拉曼晶体学方法。高分辨率晶体学研究提出了各种不同的临床相关的b-内酰胺酶类，包括KPC-2，最近与一个K。纽约爆发的肺炎、SHV-1和OXA-1、OXA-10和OXA-24/40。OXA 24/40和KPC-2都是碳青霉烯类抗生素的主要威胁。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形成稳定的抑制中间体。此外，我们正在着手使用片段混合物浸泡的b-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。我们最近结晶的卷曲螺旋结构域的鸟苷酸环化酶参与血压调节。晶体的作用是2，我们计划收集一个SeMet MAD数据集。最后，我们结晶了几个环核苷酸结合域的离子通道，我们确定了一个的结构，并有衍射晶体的其他两个。后一个项目旨在为涉及血压调节，骨生长和其他重要生理过程的环核苷酸信号通路提供结构见解。

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.