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PDBsum entry 8est
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Hydrolase(serine proteinase)
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PDB id
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8est
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Reaction of porcine pancreatic elastase with 7-Substituted 3-Alkoxy-4-Chloroisocoumarins: design of potent inhibitors using the crystal structure of the complex formed with 4-Chloro-3-Ethoxy-7-Guanidinoisocoumarin.
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Authors
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J.C.Powers,
J.Oleksyszyn,
S.L.Narasimhan,
C.M.Kam.
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Ref.
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Biochemistry, 1990,
29,
3108-3118.
[DOI no: ]
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PubMed id
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Abstract
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The crystal structure of the acyl enzyme formed upon inhibition of porcine
pancreatic elastase (PPE) by 4-chloro-3-ethoxy-7-guanidinoisocoumarin has been
determined at a 1.85-A effective resolution. The chlorine atom is still present
in this acyl enzyme, in contrast to the previously reported structure of the
7-amino-4-chloro-3-methoxyisocoumarin-PPE complex where the chlorine atom has
been replaced by an acetoxy group. The guanidino group forms hydrogen bonds with
the carbonyl group and side-chain hydroxyl group of Thr-41, and the acyl
carbonyl group has been twisted out of the oxyanion hole. Molecular modeling
indicates that the orientation of the initial Michaelis enzyme-inhibitor complex
is quite different from that of the acyl enzyme since simple reconstruction of
the isocoumarin ring would result in unfavorable interactions with Ser-195 and
His-57. Molecular models were used to design a series of new 7-(alkylureido)-
and 7-(alkylthioureido)-substituted derivatives of
3-alkoxy-7-amino-4-chloroisocoumarin as PPE inhibitors. All the
3-ethoxyisocoumarins were better inhibitors than those in the 3-methoxy series
due to better interactions with the S1 pocket of PPE. The best ureido inhibitor
also contained a tert-butylureido group at the 7-position of the isocoumarin.
Due to a predicted interaction with a small hydrophobic pocket on the surface of
PPE, this isocoumarin and a related phenylthioureido derivative are among the
best irreversible inhibitors thus far reported for PPE (kobs/[I] = 8100 M-1 s-1
and 12,000 M-1 s-1). Kinetic studies of the stability of enzyme-inhibitor
complexes suggest that many isocoumarins are alkylating the active site
histidine at pH 7.5 via a quinone imine methide intermediate, while at pH 5.0,
the predominant pathway appears to be simple formation of a stable acyl enzyme
derivative.
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Secondary reference #1
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Title
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Effect of the 7-Amino substituent on the inhibitory potency of mechanism-Based isocoumarin inhibitors for porcine pancreatic and human neutrophil elastases: a 1.85-A X-Ray structure of the complex between porcine pancreatic elastase and 7-[(N-Tosylphenylalanyl)amino]-4-Chloro-3- Methoxyisocoumarin.
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Authors
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M.A.Hernandez,
J.C.Powers,
J.Glinski,
J.Oleksyszyn,
J.Vijayalakshmi,
E.F.Meyer.
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Ref.
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J Med Chem, 1992,
35,
1121-1129.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Structural study of porcine pancreatic elastase complexed with 7-Amino-3-(2-Bromoethoxy)-4-Chloroisocoumarin as a nonreactivatable doubly covalent enzyme-Inhibitor complex.
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Authors
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J.Vijayalakshmi,
E.F.Meyer,
C.M.Kam,
J.C.Powers.
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Ref.
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Biochemistry, 1991,
30,
2175-2183.
[DOI no: ]
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PubMed id
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Secondary reference #3
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Title
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The 2.2-Angstrom resolution X-Ray crystal structure of the complex of trypsin inhibited by 4-Chloro-3-Ethoxy-7-Guanidinoisocoumarin: a proposed model of the thrombin-Inhibitor complex
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Authors
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M.M.Chow,
E.F.Meyer Junior,
W.Bode,
C.-M.Kam,
R.Radhakrishnan,
J.Vijayalakshmi,
J.C.Powers.
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Ref.
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j am chem soc, 1990,
112,
7783.
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Secondary reference #4
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Title
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Human leukocyte and porcine pancreatic elastase: X-Ray crystal structures, Mechanism, Substrate specificity, And mechanism-Based inhibitors.
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Authors
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W.Bode,
E.Meyer,
J.C.Powers.
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Ref.
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Biochemistry, 1989,
28,
1951-1963.
[DOI no: ]
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PubMed id
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Secondary reference #5
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Title
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Crystal structures of the complex of porcine pancreatic elastase with two valine-Derived benzoxazinone inhibitors.
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Authors
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R.Radhakrishnan,
L.G.Presta,
E.F.Meyer,
R.Wildonger.
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Ref.
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J Mol Biol, 1987,
198,
417-424.
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PubMed id
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Secondary reference #6
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Title
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Stereospecific reaction of 3-Methoxy-4-Chloro-7-Amino-Isocoumarin with crystalline porcine pancreatic elastase
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Authors
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E.F.Meyer Junior,
L.G.Presta,
R.Radhakrishnan.
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Ref.
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j am chem soc, 1985,
107,
4091.
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