Structural Studies of Protein Caspase Inhibitors

蛋白质半胱天冬酶抑制剂的结构研究

• 批准号: 7005403
• 负责人: Hao Wu
• 金额: $ 33.1万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7005403
• 关键词: Baculoviridae; X ray crystallography; apoptosis; chemical kinetics; computer simulation; crystallization; cysteine endopeptidases; enzyme complex; enzyme inhibitors; enzyme structure; mass spectrometry; molecular dynamics; mutant; site directed mutagenesis; structural biology; virus protein

DESCRIPTION (provided by applicant): Apoptosis is a highly regulated process that is essential for normal development and homeostasis of multicellular organisms. During viral infection, apoptosis is also a central point of interplay between the virus and the host. The characteristic features of apoptotic cell death are realized through the action of caspases, a family of conserved novel cysteine proteases. Both viral and cellular proteins have been identified that regulate apoptosis through caspase inhibition. Most notably, the p35 protein from baculoviruses is an effective and wide-spectrum caspase inhibitor that blocks apoptosis induced by numerous stimuli and in diverse organisms. Transgenic expression of p35 shows immense promise in controlling degenerative diseases. The inhibitors of apoptosis proteins (IAPs) comprise the largest family of protein caspase inhibitors, of which the X-linked IAP (XIAP) is the prototypical member. XIAP contains three tandem BIR repeats and a RING domain and exhibits specific anti-caspase activity. The involvement of IAPs in human diseases has also been suggested. A thorough understanding of caspase inhibition by protein caspase inhibitors requires structural studies of caspase/inhibitor complexes. In this proposal, we intend to determine crystal structures of several such complexes and to complement these structural studies with biochemical and mutational experiments.

描述（由申请人提供）：凋亡是一个高度调节的过程 这对于多细胞的正常发展和稳态至关重要 有机体。在病毒感染期间，凋亡也是 病毒与宿主之间的相互作用。特征的特征 凋亡细胞死亡是通过胱天蛋白酶的作用来实现的 保守的新型半胱氨酸蛋白酶。病毒蛋白和细胞蛋白均已 确定通过caspase抑制来调节细胞凋亡。最值得注意的是 杆状病毒的p35蛋白是一种有效而广谱的caspase 抑制剂阻止了许多刺激诱导的凋亡和不同的抑制剂 有机体。 p35的转基因表达在控制方面显示出巨大的希望 退化性疾病。凋亡蛋白（IAP）的抑制剂包括 最大的蛋白质caspase抑制剂家族，其中X连锁IAP（XIAP） 是原型成员。 XIAP包含三个串联BIR重复和一个环 结构域并表现出特定的抗命酶活性。 IAP参与 还建议人类疾病。 对蛋白质caspase抑制剂的caspase抑制作用的彻底了解 需要胱天蛋白酶/抑制剂复合物的结构研究。在此提案中， 我们打算确定几种此类复合物的晶体结构和 通过生化和突变补充这些结构研究 实验。