4VGC

GAMMA-CHYMOTRYPSIN D-NAPHTHYL-1-ACETAMIDO BORONIC ACID INHIBITOR COMPLEX

Summary for 4VGC

• Entry DOI: 10.2210/pdb4vgc/pdb
• Descriptor: GAMMA CHYMOTRYPSIN, SULFATE ION, D-1-NAPHTHYL-2-ACETAMIDO-ETHANE BORONIC ACID, ... (6 entities in total)
• Functional Keywords: hydrolase, serine protease
• Biological source: Bos taurus (cattle); More
• Cellular location: Secreted, extracellular space: P00766 P00766 P00766
• Total number of polymer chains: 3
• Total formula weight: 25728.79

Authors

Stoll, V.S.,Eger, B.T.,Hynes, R.C.,Martichonok, V.,Jones, J.B.,Pai, E.F. (deposition date: 1997-05-01, release date: 1997-11-12, Last modification date: 2023-08-09)

Primary citation

Stoll, V.S.,Eger, B.T.,Hynes, R.C.,Martichonok, V.,Jones, J.B.,Pai, E.F.
Differences in binding modes of enantiomers of 1-acetamido boronic acid based protease inhibitors: crystal structures of gamma-chymotrypsin and subtilisin Carlsberg complexes.
Biochemistry, 37:451-462, 1998

PubMed Abstract: 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.

PubMed: 9425066
DOI: 10.1021/bi971166o

Experimental method

X-RAY DIFFRACTION (2.1 Å)