STRUCTURAL STUDIES OF HIV-1 RT AND RNAP

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。 通过对药物靶标的三维结构的详细了解，可以帮助开发改进的药物靶标抑制剂。使用在BNL-NSLS，bemline X25收集的数据，我们计划确定HIV-1RT的结构，在存在和不存在RNA/DNA和DNA/DNA的情况下，与各种抑制剂的复合体包括：核苷/核苷酸类似物(NRTI)、特异性RNase H抑制剂(RNHI)和非核苷RT抑制剂(NNRTI)，这将使潜在的抗HIV新药的基于结构的设计成为可能。此外，我们计划利用HIV-1 RT的高分辨率X射线晶体结构来进行药物片段鸡尾酒筛选项目，旨在为现有的药物结合部位识别新的先导化合物，以及发现新的抑制剂结合口袋。我们还计划对细菌RNA聚合酶(RNAP)在各种核酸结构和抗生素复合物中的结构进行研究，以扩大我们对这些化合物对RNAP功能抑制行为的理解。

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 improved inhibitors of a drug target can be aided by detailed knowledge of its three-dimensional structure. Using data collected at BNL-NSLS, bemline X25 we plan to determine structures of HIV-1 RT in the presence and absence of both RNA/DNA and DNA/DNA in complex with a variety of inhibitors including: nucleoside/nucleotide analogs (NRTIs), specific RNase H inhibitors (RNHIs), and non-nucleoside RT inhibitors (NNRTIs) that would enable structure-based design of potential new anti-HIV drugs. Additionally we plan to use high resolution X-ray crystal structures of HIV-1 RT to carry out a drug fragment cocktail screening project designed to identify new lead compounds for existing drug-binding sites as well as discovering new inhibitor binding pockets. We also plan to pursue structural studies of bacterial RNA polymerase (RNAP) in complexes with various nucleic acid constructs and antibiotics to expand our understanding of the inhibitory behavior of these compounds on RNAP function.