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首页> 外文期刊>Biochemistry >Structural and functional analysis of caspase active sites.
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Structural and functional analysis of caspase active sites.

机译：半胱天冬酶活性位点的结构和功能分析。

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Amino acid sequences of caspases 1, 3, 7, and 8 were aligned with their published three-dimensional (3D) structures. The resultant alignment was used as a template to compare the primary structures of caspases 2, 4-6, and 9-11 to build 3D homology models. The structural models were subsequently refined and validated using structure-activity relationship data obtained from an array of substrate-like inhibitors. All caspases were shown to have identical S1 and catalytic dyad architecture but diverse S2-S4 structures. S2 pockets of these 11 caspases can be briefly categorized into two groups: Csp3, -6, and -7 as one and Csp1, -2, -4, -5, -8, -9, -10, and -11 as the other. S2 pockets of Csp3, -6, and -7 are smaller than those of the other eight caspases, and are limited to binding small P2 residues such as Ala and Val. At the S3 site, the presence of a conserved Arg in all caspases suggests that Glu would be a universally preferred P3 residue. Csp8 and Csp9 have an additional Arg in this pocket that can further enhance the binding of a P3 Glu, whereas Csp2 has a Glu adjacent to the conserved Arg. As such, Csp2 is the only caspase that can accommodate both positively and negatively charged P3. At S4, Csp1, -4, -5, and -11 are closely related with respect to their structures and binder preferences; all have a large hydrophobic pocket and prefer large hydrophobic residues such as Trp. S4 of Csp2, -3, and -7 represents an opposite group with a conformation that is highly specific in binding an Asp. The S4 structures of Csp6, -8, -9, and -10 appear to be hybrids of the two extremes, and have little specificity for any P4. Information revealed from this work provides a guide for designing potent caspase inhibitors with desirable specificity.
机译：半胱天冬酶1、3、7和8的氨基酸序列与它们公开的三维（3D）结构比对。所得的比对用作模板以比较胱天蛋白酶2、4-6和9-11的主要结构以建立3D同源性模型。随后使用从一系列底物样抑制剂获得的结构-活性关系数据对结构模型进行完善和验证。显示所有胱天蛋白酶具有相同的S1和催化二元结构，但具有不同的S2-S4结构。这11个半胱氨酸蛋白酶的S2口袋可以简要地分为两类：Csp3，-6和-7作为一类，Csp1，-2，-4，-5，-8，-9，-10和-11作为一类。其他。 Csp3，-6和-7的S2口袋比其他八个胱天蛋白酶的S2口袋要小，并且仅限于结合小的P2残基（例如Ala和Val）。在S3位点，所有胱天蛋白酶中均存在保守的Arg，这表明Glu将是普遍优选的P3残基。 Csp8和Csp9在此口袋中有一个额外的Arg，可以进一步增强P3 Glu的结合，而Csp2的Glu与保守的Arg相邻。因此，Csp2是唯一可以同时容纳带正电荷和带负电荷的P3的胱天蛋白酶。在S4，Csp1，-4，-5和-11就其结构和粘合剂偏好而言密切相关。均具有大的疏水口袋，并且优选大的疏水残基，例如Trp。 Csp2，-3和-7的S4代表相反的基团，其构象在结合Asp中具有高度特异性。 Csp6，-8，-9和-10的S4结构似乎是两个极端的混合体，对任何P4的特异性都很少。这项工作揭示的信息为设计具有所需特异性的强力半胱天冬酶抑制剂提供了指导。

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