AIDS RELATED PROTEINS--STRUCTURE AND FUNCTION

艾滋病相关蛋白质——结构和功能

• 批准号: 2573113
• 负责人: D R DAVIES
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2573113
• 关键词: X ray crystallography; crystallization; endopeptidases; human immunodeficiency virus; integrase; intermolecular interaction; oligonucleotides; protease inhibitor; protein structure function; virus protein

1. HIV integrase The recent encouraging results from the application of a multiple target drug strategy for HIV suggests that addition of a third target, the HIV integrase, might be even more effective in evading viral drug resistance through mutation. We have been engaged in a structural analysis of this enzyme and have previously reported the crystallization and structure determination of the catalytic core domain, residues 50-212. We have now crystallized this core domain in a different crystal form that reveals more details about some of the residues that were disordered in the original structure. We have also prepared a variety of other fragments of the integrase in an effort to crystallize the core domain coupled to either or both of the remaining domains. Some encouraging results have been obtained but diffraction quality crystals have not yet been produced. A method has been developed for studying the binding of the integrase to a variety of oligonucleotides and crystallization attempts are being carried out on the likely candidates. We are also attempting to obtain crystals of complexes of the integrase with a variety of inhibitors. 2. The HIV protease. We have examined the crystal structures of several complexes of the HIV protease complexed with several peptides that bind to the enzyme and inhibits its activity. The results are unusual in that there is cleavage of the octapeptide and apparent binding of the N-terminal pentapeptide, representing product inhibition of the enzyme.

1. HIV整合酶 最近令人鼓舞的结果，从应用的多个 艾滋病毒靶向药物战略建议增加第三个靶点， HIV整合酶可能更有效地逃避病毒药物 通过突变来抵抗 我们一直在进行一场结构性的 这种酶的分析和以前的报道， 催化核的结晶和结构测定 结构域，残基50-212。 我们现在已经明确了这个核心领域， 一种不同的晶体形式，揭示了更多的细节， 在原始结构中无序的残基。 我们还 制备了整合酶的各种其他片段， 使耦合到剩余的一个或两个的核心域结晶 域. 已经取得了一些令人鼓舞的结果， 还没有生产出高质量的晶体。 了一种方法 开发用于研究整合酶与多种 寡核苷酸和结晶尝试正在进行 可能的候选人。我们还试图获得 整合酶与多种抑制剂的复合物。 2. HIV蛋白酶 我们已经研究了几个配合物的晶体结构， HIV蛋白酶与几种结合酶的肽复合 并抑制其活性。 结果是不寻常的， 八肽的切割和N-末端的表观结合 五肽，代表酶的产物抑制。