STRUCTURE & FUNCTION ANALYSIS OF KAPOSIS SARCOMA ASSOCIATED PROTEASE: AIDS

卡波西肉瘤是一种常见的艾滋病相关肿瘤， 与最近发现的一种 人类疱疹病毒（HHV-8）。 HHV-8，也称为卡波西氏病 肉瘤相关疱疹病毒（KSHV）需要协同活动， 病毒编码的蛋白酶（Pr）及其底物的组装， 蛋白（AP）。 这种蛋白酶似乎利用结构和 底物识别基序与其他丝氨酸完全不同 蛋白酶，如胰凝乳蛋白酶和枯草杆菌蛋白酶家族的那些。 这些后一类酶已经被本领域的技术人员广泛研究。 Craik组;这种以前的知识应该显着帮助 KSHV Pr的组装、结构 底物识别和催化机制。 实际上，积极的， Craik实验室现在可用的纯化酶已经导致了有希望的 这些领域的初步进展。 此外， 这种Pr与通常合并感染的人类免疫缺陷 病毒正在探索中，小分子的合理设计 和KSHV成熟活性的显性负抑制剂 公关将以类似的方式进行。 在所有这些问题中， 酶的结构、机制和抑制剂设计， 计算机图形实验室已被证明是一个宝贵的工具， 开发药物策略以缓解 艾滋病患者的卡波西肉瘤

Kaposi's Sarcoma, a common AIDS-associated neoplasm, has been correlated with the infection and replication of a recently identified human herpesvirus (HHV-8). HHV-8, also known as Kaposi's sarcoma-associated herpesvirus (KSHV) requires the concerted activity of a virally-encoded protease (Pr) and its substrate, the assembly protein (AP). This protease appears to utilize structural and substrate recognition motifs quite different from other serine proteases, such as those of the chymotrypsin and subtilisin families. These latter classes of enzymes have been extensively studied by the Craik group; such previous knowledge should aid remarkably in the elucidation of the molecular details of KSHV Pr's assembly, structure, substrate recognition, and catalytic mechanism. Indeed, the active, purified enzyme now available in the Craik lab has led to promising initial advances in these areas. In addition, the relationship of this Pr to that of the commonly co-infected human immunodeficiency virus is being explored, and the rational design of small-molecule and dominant-negative inhibitors of the maturational activity of KSHV Pr will be pursued in an analogous fashion. In all these questions of enzyme structure, mechanism, and inhibitor design, the resources of the Computer Graphics Laboratory have proved an invaluable tool for developing pharmaceutical strategies to alleviate the progression of Kaposi's Sarcoma in AIDS patients.