F1L

F1L

• 批准号: 7358881
• 负责人: PETER M COLMAN
• 金额: $ 0.24万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7358881
• 关键词: F1L

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. Bak is a member of the executioner-faction of the Bcl-2 protein family. Its function is normally antagonised by the Bcl-2 homologue Mcl-1, and Mcl-1 function is itself antagonised by the so-called BH3-only proteins that transmit various stress stimuli to the apoptotic machinery. M11L and F1L are viral inhibitors of programmed cell death (apoptosis) from Myxoma virus and Vaccinia virus, respectively. Both M11L and F1L appear to act on the mitochondrial pathway to apoptosis by targeting Bak. Despite the ability of M11L and F1L to bind Bak, neither has a detectable sequence homology to the Bcl-2 family of proteins or indeed to any other protein of known 3-D structure. Viruses are dependent on their host to ensure their own proliferation and propagation. Programmed cell death or apoptosis is an important mechanism employed by host immune systems to combat viral infections and prevent their spread. Viruses employ several strategies to counter host immune responses, including expression of viral pro-survival proteins that inhibit apoptosis of host cells. M11L and F1L are viral proteins that potently inhibit apoptosis by interfering with the mitochondrial-dependent intrinsic pathway of apoptosis by targeting Bak. Over-expression of M11L is sufficient to prevent apoptosis after suitable death stimuli by inhibiting MMP. We have obtained crystals for M11L both in the presence and absence of a human Bak 26-mer peptide, as well as crystals for F1L. Structural studies of the molecular control of Bak will inform efforts to discover drugs that can, on the one hand, bypass dysfunctional upstream cues that prevent many cancer cells from entering apoptosis, or, on the other, prevent untimely apoptosis associated with some degenerative disorders.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。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，不一定是研究者所在机构。巴克是Bcl-2蛋白家族中的执行者。它的功能通常被Bcl-2同源物Mcl-1拮抗，而Mcl-1功能本身被所谓的仅BH 3蛋白拮抗，该蛋白将各种应激刺激传递到凋亡机制。M11 L和F1 L分别是来自粘液瘤病毒和牛痘病毒的程序性细胞死亡（凋亡）的病毒抑制剂。M11 L和F1 L似乎都通过靶向巴克作用于线粒体凋亡途径。尽管M11 L和F1 L具有结合巴克的能力，但它们与Bcl-2蛋白家族或任何其他已知3-D结构的蛋白都没有可检测的序列同源性。病毒依赖于其宿主来确保其自身的增殖和繁殖。程序性细胞死亡或细胞凋亡是宿主免疫系统对抗病毒感染并防止其传播的重要机制。病毒采用几种策略来对抗宿主免疫应答，包括表达抑制宿主细胞凋亡的病毒促存活蛋白。M11 L和F1 L是通过靶向巴克干扰细胞凋亡的细胞依赖性内在途径而有效抑制细胞凋亡的病毒蛋白。M11 L的过表达足以通过抑制MMP来防止合适的死亡刺激后的细胞凋亡。我们已经在存在和不存在人巴克26-聚体肽的情况下获得了M11 L的晶体，以及F1 L的晶体。对巴克分子调控的结构研究将为发现药物提供信息，这些药物一方面可以绕过阻止许多癌细胞进入凋亡的功能失调的上游线索，另一方面可以防止与一些退行性疾病相关的过早凋亡。