STRUCTURAL STUDIES OF HIV-1 RT AND RNAP

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来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 药物靶标的改进抑制剂的开发可以通过其三维结构的详细知识来帮助。使用在BNL-NSLS收集的数据，bemline X25我们计划确定HIV-1 RT在RNA/DNA和DNA/DNA与各种抑制剂复合存在和不存在的情况下的结构，所述抑制剂包括：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），这将使潜在的新抗HIV药物的基于结构的设计成为可能。此外，我们计划使用HIV-1 RT的高分辨率X射线晶体结构进行药物片段鸡尾酒筛选项目，旨在为现有药物结合位点识别新的先导化合物，并发现新的抑制剂结合口袋。我们还计划进行细菌RNA聚合酶（RNAP）与各种核酸构建体和抗生素复合物的结构研究，以扩大我们对这些化合物对RNAP功能的抑制行为的理解。

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.