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Titolo:
STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR-D
Autore:
COLE LB; KILPATRICK JM; CHU NM; BABU YS;
Indirizzi:
ABBOTT LABS,DIV DIAGNOST,POB 152020,1921 HURD DR IRVING TX 75015 BIOCRYST PHARMACEUT INC BIRMINGHAM AL 35244
Titolo Testata:
Acta crystallographica. Section D, Biological crystallography
, volume: 54, anno: 1998,
parte:, 5
pagine: 711 - 717
SICI:
0907-4449(1998)54:<711:SO3F>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
ALTERNATIVE COMPLEMENT PATHWAY; FREE R-VALUE; ISOCOUMARIN INHIBITORS; CRYSTAL-STRUCTURES; ACTIVE-SITE; PROTEIN-D; SYSTEM; RESOLUTION; MECHANISM; ELASTASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
28
Recensione:
Indirizzi per estratti:
Citazione:
L.B. Cole et al., "STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR-D", Acta crystallographica. Section D, Biological crystallography, 54, 1998, pp. 711-717

Abstract

Factor D (D) is a serine protease essential in the activation of the alternative complement pathway. Only a few of the common serine protease inhibitors inhibit D, binding covalently to the serine hydroxyl of the catalytic triad. 3,4-Dichloroisocoumarin (DCI) is a mechanism-based inhibitor which inhibits most serine proteases and many esterases, including D. The structure of the enzyme:inhibitor covalent adduct of Dwith DCI, DCI:D, to a resolution of 1.8 Angstrom is described, which represents the first structural analysis of D with a mechanism-based inhibitor. The side chain of the ring-opened DCI moiety of the protein adduct undergoes chemical modification in the buffered solution, resulting in the formation of an cr-hydroxy acid moiety through the nucleophilic substitution of both Cl atoms. The inhibited enzyme is similar in overall structure to the native enzyme, as well as to a variety of isocoumarin-inhibited trypsin and porcine pancreatic elastase (PPE) structures, yet notable differences are observed in the active site and binding mode of these small-molecule inhibitors. One region of the active site (residues 189-195) is relatively conserved between factor D, trypsin, and elastase with respect to amino-acid sequence and to conformation. Another region (residues 214-220) reflects the amino-acid substitutions and conformational flexibility between these enzymes. The carbonyl O atom of the DCI moiety was found to be oriented away from theoxyanion hole, which greatly contributes to the stability of the DCI:D adduct. The comparisons of the active sites between native factor D,DCI-inhibited factor D, and various inhibited trypsin and elastase (PPE) molecules are providing the chemical bases directing the design ofnovel, small-molecule pharmaceutical agents capable of modulating thealternative complement pathway.

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Documento generato il 26/09/20 alle ore 17:48:03