F1L

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。Bak是Bcl2蛋白家族中的刽子手派别的成员。它的功能通常被Bcl2同系物Mcl-1拮抗，Mcl-1功能本身也被所谓的BH3-Only蛋白拮抗，这些蛋白将各种应激刺激传递给细胞凋亡机制。M11L和F1L分别是粘液瘤病毒和痘苗病毒程序性细胞死亡(细胞凋亡)的病毒抑制剂。M11L和F1L似乎都通过靶向Bak作用于线粒体的凋亡途径。尽管M11L和F1L有结合Bak的能力，但两者都没有可检测到的序列与Bcl2蛋白家族或任何其他已知三维结构的蛋白质同源。病毒依赖于它们的宿主来确保自己的繁殖和传播。细胞程序性死亡或凋亡是宿主免疫系统用来对抗病毒感染和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反应，包括表达抑制宿主细胞凋亡的病毒亲生存蛋白。M11L和F1L是病毒蛋白，通过靶向Bak来干扰线粒体依赖的内在凋亡途径，从而有效地抑制细胞凋亡。在适当的死亡刺激下，M11L的过度表达足以通过抑制基质金属蛋白酶来防止细胞凋亡。在人Bak26-肽存在和不存在的情况下，我们都获得了M11L的晶体，以及F1L的晶体。对Bak分子控制的结构研究将为发现药物的努力提供信息，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信号，或者另一方面，防止与某些退行性疾病相关的过早凋亡。

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.