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Titolo:
Crystal structure of gamma-chymotrypsin in complex with 7-hydroxycoumarin
Autore:
Ghani, U; Ng, KKS; Atta-ur-Rahman; Choudhary, MI; Ullah, N; James, MNG;
Indirizzi:
Univ Alberta, CIHR, Grp Prot Struct & Funct, Dept Biochem, Edmonton, AB T6G 2H7, Canada Univ Alberta Edmonton AB Canada T6G 2H7 hem, Edmonton, AB T6G 2H7, Canada Univ Karachi, Int Ctr Chem Sci, Chem Res Inst, Karachi 75270, Pakistan Univ Karachi Karachi Pakistan 75270 em Res Inst, Karachi 75270, Pakistan
Titolo Testata:
JOURNAL OF MOLECULAR BIOLOGY
fascicolo: 3, volume: 314, anno: 2001,
pagine: 519 - 525
SICI:
0022-2836(20011130)314:3<519:CSOGIC>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
PORCINE PANCREATIC ELASTASE; HUMAN-LEUKOCYTE ELASTASE; ALPHA-CHYMOTRYPSIN; SERINE PROTEASES; INHIBITORS; MECHANISM; INACTIVATION; 3-BENZYL-6-CHLORO-2-PYRONE; CRYSTALLOGRAPHY; BENZOXAZINONES;
Keywords:
coumarin chymotrypsin inhibitors; 7-hydroxycoumarin; acylating agents; X-ray crystallography;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
31
Recensione:
Indirizzi per estratti:
Indirizzo: James, MNG Univ Alberta, CIHR, Grp Prot Struct & Funct, Dept Biochem, Edmonton, AB T6G 2H7, Canada Univ Alberta Edmonton AB Canada T6G 2H7 on, AB T6G 2H7, Canada
Citazione:
U. Ghani et al., "Crystal structure of gamma-chymotrypsin in complex with 7-hydroxycoumarin", J MOL BIOL, 314(3), 2001, pp. 519-525

Abstract

The 1.8 Angstrom crystal structure of 7-hydroxycoumarin (7-HC) bound to chymotrypsin reveals that this inhibitor forms a planar cinnamate acyl-enzymecomplex. The phenyl ring of the bound inhibitor forms numerous van der Waals contacts in the S1 pocket of the enzyme, with the p-hydroxyl group donating a hydrogen bond to the main-chain oxygen atom of Ser217, and the o-hydroxyl group forming a water-mediated hydrogen bond with the carbonyl oxygen of Val227. The structure of the acyl-enzyme complex suggests that the mechanism of inhibition of 7-HC involves nucleophilic attack by the Ser195 O-gamma atom on the carbonyl carbon atom of the inhibitor, accompanied by the breaking of the 2-pyrone ring of the inhibitor, and leading to the formation of a cinnamate acyl-enzyme derivative via a tetrahedral transition state. Comparisons with structures of photoreversible cinnamates bound to chymotrypsin reveal that although 7-HC interacts with the enzyme in a similar fashion, the binding of 7-HC to chymotrypsin takes place in a productive conformation in contrast to the photoreversible cinnamates. In summary, the 7-HC-chymotrypsin complex provides basic insight into the inhibition of chymotrypsin by natural coumarins and provides a structural basis for the design of more potent mechanism-based inhibitors against a wide range of biologically important chymotypsin-like enzymes. (C) 2001 Academic Press.

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Documento generato il 01/04/20 alle ore 11:05:05