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PDBsum entry 9est
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Hydrolase(serine proteinase)
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PDB id
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9est
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References listed in PDB file
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Key reference
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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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Abstract
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The complex of porcine pancreatic elastase (PPE) with
7-amino-3-(2-bromoethoxy)-4-chloroisocoumarin, a potent mechanism-based
inhibitor, was crystallized and the crystal structure determined at 1.9-A
resolution with a final R factor of 17.1%. The unbiased difference Fourier
electron density map showed continuous density from O gamma of Ser 195 to the
benzoyl carbonyl carbon atom and from N epsilon 2 of His 57 to the carbon atom
at the 4-position of the isocoumarin ring in the inhibitor. This suggested
unambiguously that the inhibitor was doubly covalently bound to the enzyme. It
represents the first structural evidence for irreversible binding of an
isocoumarin inhibitor to PPE through both Ser 195 and His 57 in the active site.
The PPE-inhibitor complex is only partially activated in solution by
hydroxylamine and confirms the existence of the doubly covalently bound complex
along with the acyl enzyme. The benzoyl carbonyl oxygen atom of the inhibitor is
not situated in the oxyanion hole formed by the amide (greater than NH) groups
of Gly 193 and Ser 195. The complex is stabilized by the hydrogen-bonding
interactions in the active site (from the N epsilon 2 of Gln 192 to the bromine
atom in the inhibitor and the amino group at the 7-position of the isocoumarin
ring to the carbonyl oxygen of Thr 41) and by van der Waals interactions. The
inhibition rates of several 7-substituted 4-chloro-3-(bromoalkoxy)isocoumarins
toward PPE were measured.(ABSTRACT TRUNCATED AT 250 WORDS)
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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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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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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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