Differences in Binding Modes of Enantiomers of 1-Acetamido Boronic Acid Based Protease Inhibitors: Crystal Structures of -Chymotryps
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- 作者：Vincent S. Stoll ; Bryan T. Eger ; Rosemary C. Hynes ; Valeri Martichonok ; J. Bryan Jones ; and Emil F. Pai
- 刊名：Biochemistry
- 出版年：1998
- 出版时间：January 13, 1998
- 年：1998
- 卷：37
- 期：2
- 页码：451 - 462
- 全文大小：296K
- 年卷期：v.37,no.2(January 13, 1998)
- ISSN：1520-4995
文摘
In order to probe the structural basis of stereoselectivity in theserine protease family, a seriesof enantiomeric boronic acidsRCH2CH(NHCOCH3)B(OH)2has been synthesized and kineticallycharacterized as transition-state analog inhibitors using
-chymotrypsin and subtilisin Carlsberg as modelsystems. When the R-substituent in this series was changed from ap-chlorophenyl to a 1-naphthyl group,-chymotrypsin, but not subtilisin, reversed its usual preference forL-enantiomers and bound more tightlyto the D-enantiomer [Martichonok, V., & Jones, J. B.(1996) J. Am. Chem. Soc.118, 950-958]. Thestructural factors responsible for the differences in stereoselectivitybetween the two enzymes have beenexplored by X-ray crystallographic examination of subtilisin Carlsbergand 
-chymotrypsin complexesof the L- and D-enantiomers ofp-chlorophenyl and 1-naphthyl boronic acid derivatives.In both enzymes,the L-isomers of the inhibitors, which are more closelyrelated to the natural L-amino acidsubstrates,form tetrahedral adducts, covalently linking the central boron atom andO of the catalytic serine. TheD-isomers, however, differ in the way they interact withsubtilisin or -chymotrypsin. With subtilisin,both the D-p-chlorophenyl andD-1-naphthyl inhibitor complexes form covalent SerO-to-boron bonds,but with -chymotrypsin, the same inhibitors lead to noveltetrahedral adducts covalently linking bothSer195 O and His57 N
2 covalently via theboron atom.
-chymotrypsin and subtilisin Carlsberg as modelsystems. When the R-substituent in this series was changed from ap-chlorophenyl to a 1-naphthyl group,-chymotrypsin, but not subtilisin, reversed its usual preference forL-enantiomers and bound more tightlyto the D-enantiomer [Martichonok, V., & Jones, J. B.(1996) J. Am. Chem. Soc.118, 950-958]. Thestructural factors responsible for the differences in stereoselectivitybetween the two enzymes have beenexplored by X-ray crystallographic examination of subtilisin Carlsbergand -chymotrypsin complexesof the L- and D-enantiomers ofp-chlorophenyl and 1-naphthyl boronic acid derivatives.In both enzymes,the L-isomers of the inhibitors, which are more closelyrelated to the natural L-amino acidsubstrates,form tetrahedral adducts, covalently linking the central boron atom andO of the catalytic serine. TheD-isomers, however, differ in the way they interact withsubtilisin or -chymotrypsin. With subtilisin,both the D-p-chlorophenyl andD-1-naphthyl inhibitor complexes form covalent SerO-to-boron bonds,but with -chymotrypsin, the same inhibitors lead to noveltetrahedral adducts covalently linking bothSer195 O and His57 N2 covalently via theboron atom.