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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Structural asymmetry of procaspase-7 bound to a specific inhibitor
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Structural asymmetry of procaspase-7 bound to a specific inhibitor

机译：结构不对称procaspase-7绑定到一个特定抑制剂

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摘要

Caspase-7 is expressed as a proenzyme and is activated by initiator caspases upon the transmission of cell-death signals. Despite extensive structural and biochemical analyses, many questions regarding the mechanism of caspase-7 activation remain unanswered. Caspase-7 is auto-activated during overexpression in Escherichia coli, even in the absence of initiator caspases, indicating that procaspase-7 has intrinsic catalytic activity. When variants of procaspase-7 with altered L2 loops were prepared, a variant with six inserted amino acids showed meaningful catalytic activity which was inhibited by Ac-DEVD-CHO. The kinetic constants of the procaspase-7 variant were determined and its three-dimensional structure was solved with and without bound inhibitor. The homodimeric procaspase-7 bound to the inhibitor revealed an asymmetry. One monomer formed a complete active site bound to the inhibitor in collaboration with the L2 loop from the other monomer, whereas the other monomer had an incomplete active site despite the bound inhibitor. Consequently, the two L2 loops in homodimeric procaspase-7 served as inherent L2 and L2′ loops forming one complete active site. These data represent the first three-dimensional structure of a procaspase-7 variant bound to a specific inhibitor, Ac-DEVD-CHO, and provide insight into the folding mechanism during caspase-7 activation and the basal activity level of procaspase-7.
机译：Caspase-7酶原和表达激活启动程序还在细胞死亡信号的传播。广泛的结构和生化分析,许多问题的机制caspase-7激活仍然悬而未决。超表达中自动激活它吗大肠杆菌,甚至没有引发剂还存在,这表明procaspase-7有内在的催化活性。与改变procaspase-7 L2循环准备好了,有六个氨基酸插入一个变体显示有意义的的催化活性由Ac-DEVD-CHO抑制。的测定和procaspase-7变体它的三维结构是解决如果没有绑定抑制剂。procaspase-7绑定到抑制剂了不对称。网站绑定到抑制剂合作其他单体的L2循环,而其他单体有一个不完整的活性部位尽管抑制剂。两个L2循环homodimeric procaspase-7服务固有的L2和L2的循环形成一个完整的活跃的站点。procaspase-7的三维结构变量绑定到一个特定的抑制剂,Ac-DEVD-CHO,并提供洞察折叠在caspase-7激活和机制基底procaspase-7的活动水平。

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