Differences in binding modes of enantiomers of 1-acetamido boronic acid based protease inhibitors: crystal structures of gamma-chymotrypsin and subtilisin Carlsberg complexes.
Differences in binding modes of enantiomers of 1-acetamido boronic acid based protease inhibitors: crystal structures of gamma-chymotrypsin and subtilisin Carlsberg complexes.
复制标题
1-乙酰氨基硼酸蛋白酶抑制剂对映体结合模式的差异：γ-胰凝乳蛋白酶和枯草杆菌蛋白酶嘉士伯复合物的晶体结构。
DOI：
10.1021/bi971166o
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发表时间：
1998
期刊：
影响因子：
2.9
通讯作者：
Emil F. Pai
中科院分区：
文献类型：
--
作者：
Vincent S. Stoll;B. Eger;Rosemary C. Hynes;V. Martichonok;J. Bryan Jones;Emil F. Pai
为了探索丝氨酸蛋白酶家族中立体选择性的结构基础，以α-糜蛋白酶和枯草杆菌蛋白酶Carlsberg为模型体系，合成了一系列对映体硼酸RCH 2CH（NHCOCH 3）B（OH）2，并对其进行了动力学表征.当该系列中的R-取代基从对氯苯基变为1-萘基时，α-胰凝乳蛋白酶而不是枯草杆菌蛋白酶逆转其通常对l-对映异构体的偏好并更紧密地结合D-对映异构体[Martichonok，V.，& Jones，J. B.等人（1996）J. Am. 118，950-958]。负责的两种酶之间的立体选择性的差异的结构因素已被探索的枯草杆菌蛋白酶嘉士伯和γ-胰凝乳蛋白酶复合物的L-和D-对映体的p-氯苯基和1-萘基硼酸衍生物的X-射线晶体学检查。在这两种酶中，抑制剂的L-异构体与天然L-氨基酸底物更密切相关，形成四面体加合物，共价连接中心硼原子和催化丝氨酸的Ogamma。然而，d-异构体与枯草杆菌蛋白酶或γ-糜蛋白酶相互作用的方式不同。与枯草杆菌蛋白酶，D-对-氯苯基和D-1-萘基抑制剂复合物形成共价Ser O-到-硼键，但与γ-胰凝乳蛋白酶，相同的抑制剂导致新的四面体加合物共价连接Ser 195 O-和His 57 Nepsilon 2通过硼原子共价。
In order to probe the structural basis of stereoselectivity in the serine protease family, a series of enantiomeric boronic acids RCH2CH(NHCOCH3)B(OH)2 has been synthesized and kinetically characterized as transition-state analog inhibitors using alpha-chymotrypsin and subtilisin Carlsberg as model systems. When the R-substituent in this series was changed from a p-chlorophenyl to a 1-naphthyl group, alpha-chymotrypsin, but not subtilisin, reversed its usual preference for l-enantiomers and bound more tightly to the D-enantiomer [Martichonok, V., & Jones, J. B. (1996) J. Am. Chem. Soc. 118, 950-958]. The structural factors responsible for the differences in stereoselectivity between the two enzymes have been explored by X-ray crystallographic examination of subtilisin Carlsberg and gamma-chymotrypsin complexes of the L- and D-enantiomers of p-chlorophenyl and 1-naphthyl boronic acid derivatives. In both enzymes, the L-isomers of the inhibitors, which are more closely related to the natural L-amino acid substrates, form tetrahedral adducts, covalently linking the central boron atom and Ogamma of the catalytic serine. The d-isomers, however, differ in the way they interact with subtilisin or gamma-chymotrypsin. With subtilisin, both the D-p-chlorophenyl and D-1-naphthyl inhibitor complexes form covalent Ser Ogamma-to-boron bonds, but with gamma-chymotrypsin, the same inhibitors lead to novel tetrahedral adducts covalently linking both Ser195 Ogamma and His57 Nepsilon2 covalently via the boron atom.