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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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Contents |
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.21.36
- pancreatic elastase.
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Reaction:
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Hydrolysis of proteins, including elastin. Preferential cleavage: Ala-|-Xaa.
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DOI no:
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Biochemistry
30:2175-2183
(1991)
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PubMed id:
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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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J.Vijayalakshmi,
E.F.Meyer,
C.M.Kam,
J.C.Powers.
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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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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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K.R.Vinothkumar,
K.Strisovsky,
A.Andreeva,
Y.Christova,
S.Verhelst,
and
M.Freeman
(2010).
The structural basis for catalysis and substrate specificity of a rhomboid protease.
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EMBO J,
29,
3797-3809.
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PDB codes:
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I.Nakanishi,
T.Kinoshita,
A.Sato,
and
T.Tada
(2000).
Structure of porcine pancreatic elastase complexed with FR901277, a novel macrocyclic inhibitor of elastases, at 1.6 A resolution.
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Biopolymers,
53,
434-445.
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PDB code:
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P.Taylor,
V.Anderson,
J.Dowden,
S.L.Flitsch,
N.J.Turner,
K.Loughran,
and
M.D.Walkinshaw
(1999).
Novel mechanism of inhibition of elastase by beta-lactams is defined by two inhibitor crystal complexes.
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J Biol Chem,
274,
24901-24905.
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A.Rossi,
G.Elia,
and
M.G.Santoro
(1998).
Activation of the heat shock factor 1 by serine protease inhibitors. An effect associated with nuclear factor-kappaB inhibition.
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J Biol Chem,
273,
16446-16452.
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P.D.Edwards,
and
P.R.Bernstein
(1994).
Synthetic inhibitors of elastase.
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Med Res Rev,
14,
127-194.
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D.Solís,
P.Fernández,
T.Díaz-Mauriño,
J.Jiménez-Barbero,
and
M.Martín-Lomas
(1993).
Hydrogen-bonding pattern of methyl beta-lactoside binding to the Ricinus communis lectins.
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Eur J Biochem,
214,
677-683.
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H.Djaballah,
J.A.Harness,
P.J.Savory,
and
A.J.Rivett
(1992).
Use of serine-protease inhibitors as probes for the different proteolytic activities of the rat liver multicatalytic proteinase complex.
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Eur J Biochem,
209,
629-634.
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M.Wakselman,
R.Joyeau,
R.Kobaiter,
N.Boggetto,
I.Vergely,
J.Maillard,
V.Okochi,
J.J.Montagne,
and
M.Reboud-Ravaux
(1991).
Functionalized N-aryl azetidinones as novel mechanism-based inhibitors of neutrophil elastase.
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FEBS Lett,
282,
377-381.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
