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首页> 外文期刊>Journal of Molecular Biology >Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex.
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Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex.

机译：在位点S（4）处探测到的caspase-8特异性：caspase-8-Z-DEVD-cho复合物的晶体结构。

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摘要

Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the downstream executioner caspase-3 is a physiological target. Caspases are cysteine proteases that are specific for substrates with an aspartic acid residue at the P(1) position and have an optimal recognition motif that incorporates four amino acid residues N-terminal to the cleavage site. Caspase-8 has been classified as a group III caspase member because it shows a preference for a small hydrophobic residue at the P(4) substrate position. We report the X-ray crystallographic structure of caspase-8 in complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a specific group II caspase inhibitor. The structure shows that the inhibitor interacts favourably with the enzyme in subsite S(4). Kinetic data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1 nM). In view of this finding, the original classification of caspases into three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue Asp in subsite S(4). We propose that the subsite S(3) must be considered as an important specificity-determining factor. Copyright 2000 Academic Press.
机译：Caspase-8是Fas介导的途径中的起始酶，下游执行者caspase-3是生理靶标。胱天蛋白酶是半胱氨酸蛋白酶，其对在P（1）位置具有天冬氨酸残基的底物具有特异性，并具有最佳识别基序，该基序并入了裂解位点N端的四个氨基酸残基。 Caspase-8已被分类为III类caspase成员，因为它在P（4）底物位置显示较小的疏水残基。我们报告了caspase-8与苄氧基羰基-Asp-Glu-Val-Asp-醛（Z-DEVD）（一种特定的II类caspase抑制剂）复合的X射线晶体学结构。结构表明该抑制剂与位点S（4）中的酶相互作用良好。动力学数据表明，Z-DEVD（K（i）2 nM）是caspase-8抑制剂，与特定的III组抑制剂Boc-IETD-醛（K（i）1 nM）几乎一样有效。鉴于这一发现，至少在半胱天冬酶8上，需要将半胱天冬酶分为三个特异性组的原始分类进行修改，至少可以耐受亚位点S（4）中的小的疏水性残基以及酸性残基Asp。我们建议，子站点S（3）必须被视为重要的特异性决定因素。版权所有2000学术出版社。

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