STRUCTURAL STUDIES OF ANTHRAX LETHAL TOXIN

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项工作的目的是确定炭疽致死毒素中毒的原子水平机制，并促进基于结构的抗毒素药物设计。这两种毒素成分是保护性抗原(PA)和致死因子(LF)。基于我们的PA63的水溶性七聚体的结构，我们提出了一个特定的假设，即pH诱导的构象变化导致了跨膜的β-桶的产生。我们最近完成了Lf的晶体结构，并确定了它与其细胞内靶点之一MAPKK(MAPKK)的复合体的结构。我们建议通过确定Lf与MAPKK衍生的多肽和抑制剂的络合物中的高分辨结构以及PA63的膜插入结构来扩展这项工作。

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 purpose of this work is to determine the atomic-level mechanisms of intoxication by Anthrax Lethal Toxin, and to facilitate structure-based drug design of anti-toxins. The two toxin components are Protective Antigen (PA) and Lethal Factor (LF). Based on our structure of the water-soluble heptamer of PA63 we have formulated a specific hypothesis of pH-induced conformational change leading to the creation of a membrane-spanning beta-barrel. We recently completed the crystal structure of LF and determined the structure in complex with one of its intracellular targets, MAP kinase kinase-2 (MAPKK). We propose to extend this work by determining the high resolution structures of LF in complex with MAPKK-derived peptides and inhibitors, and the membrane inserted structure of PA63.