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PDBsum entry 1pph
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Hydrolase/hydrolase inhibitor
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PDB id
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1pph
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Contents |
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.21.4
- trypsin.
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Reaction:
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Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.
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DOI no:
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FEBS Lett
287:133-138
(1991)
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PubMed id:
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Geometry of binding of the N alpha-tosylated piperidides of m-amidino-, p-amidino- and p-guanidino phenylalanine to thrombin and trypsin. X-ray crystal structures of their trypsin complexes and modeling of their thrombin complexes.
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D.Turk,
J.Stürzebecher,
W.Bode.
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ABSTRACT
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The X-ray crystal structures of the complexes formed with bovine trypsin and the
N alpha-tosylated piperidides of m-amidino-, p-amidino- and
p-guanidino-D,L-phenylalanine (3-TAPAP, 4-TAPAP and 4-TGPAP) were determined
with data to 1.8 A resolution. The L-stereoisomer of 3-TAPAP binds as a compact
entity into the active site of trypsin, with the amidino and the carbonyl groups
of the central amidinophenylalanyl residue hydrogen-bonded to Gly216 of trypsin.
According to modeling and energy minimization, 3-TAPAP fits perfectly in this
conformation to the more restrictive thrombin active site also (Bajusz et al.
(1978) Int. J. Pept. Prot. Res. 12, 217-221); the piperidine moiety extends into
the cage-like S2 subsite of thrombin, but leaves room for additional
substituents which might help to improve binding and pharmacological properties.
In contrast, 4-TAPAP and 4-TGPAP bind only weakly and in an extended
conformation to trypsin; their considerably enhanced affinities for thrombin
would suggest a more compact binding to thrombin.
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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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M.Sherawat,
P.Kaur,
M.Perbandt,
C.Betzel,
W.A.Slusarchyk,
G.S.Bisacchi,
C.Chang,
B.L.Jacobson,
H.M.Einspahr,
and
T.P.Singh
(2007).
Structure of the complex of trypsin with a highly potent synthetic inhibitor at 0.97 A resolution.
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Acta Crystallogr D Biol Crystallogr,
63,
500-507.
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PDB code:
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E.S.Henriques,
N.Fonseca,
and
M.J.Ramos
(2004).
On the modeling of snake venom serine proteinase interactions with benzamidine-based thrombin inhibitors.
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Protein Sci,
13,
2355-2369.
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E.Toyota,
H.Sekizaki,
K.Itoh,
and
K.Tanizawa
(2003).
Synthesis and evaluation of guanidine-containing Schiff base copper(II), zinc(II), and iron(III) chelates as trypsin inhibitors.
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Chem Pharm Bull (Tokyo),
51,
625-629.
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M.M.Mueller,
S.Sperl,
J.Stürzebecher,
W.Bode,
and
L.Moroder
(2002).
(R)-3-Amidinophenylalanine-derived inhibitors of factor Xa with a novel active-site binding mode.
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Biol Chem,
383,
1185-1191.
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PDB codes:
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S.M.Schwarzl,
T.B.Tschopp,
J.C.Smith,
and
S.Fischer
(2002).
Can the calculation of ligand binding free energies be improved with continuum solvent electrostatics and an ideal-gas entropy correction?
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J Comput Chem,
23,
1143-1149.
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S.Sperl,
A.Bergner,
J.Stürzebecher,
V.Magdolen,
W.Bode,
and
L.Moroder
(2000).
Urethanyl-3-amidinophenylalanine derivatives as inhibitors of factor Xa. X-ray crystal structure of a trypsin/inhibitor complex and modeling studies.
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Biol Chem,
381,
321-329.
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S.Sperl,
U.Jacob,
N.Arroyo de Prada,
J.Stürzebecher,
O.G.Wilhelm,
W.Bode,
V.Magdolen,
R.Huber,
and
L.Moroder
(2000).
(4-aminomethyl)phenylguanidine derivatives as nonpeptidic highly selective inhibitors of human urokinase.
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Proc Natl Acad Sci U S A,
97,
5113-5118.
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PDB code:
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G.S.Coombs,
M.S.Rao,
A.J.Olson,
P.E.Dawson,
and
E.L.Madison
(1999).
Revisiting catalysis by chymotrypsin family serine proteases using peptide substrates and inhibitors with unnatural main chains.
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J Biol Chem,
274,
24074-24079.
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K.Lee,
S.Y.Hwang,
M.Yun,
and
D.S.Kim
(1998).
Potent and efficacious thienylamidine-incorporated thrombin inhibitors.
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Bioorg Med Chem Lett,
8,
1683-1686.
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J.H.Matthews,
R.Krishnan,
M.J.Costanzo,
B.E.Maryanoff,
and
A.Tulinsky
(1996).
Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site.
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Biophys J,
71,
2830-2839.
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PDB codes:
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G.Klebe,
T.Mietzner,
and
F.Weber
(1994).
Different approaches toward an automatic structural alignment of drug molecules: applications to sterol mimics, thrombin and thermolysin inhibitors.
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J Comput Aided Mol Des,
8,
751-778.
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H.J.Böhm
(1994).
The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure.
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J Comput Aided Mol Des,
8,
243-256.
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W.Bode,
D.Turk,
and
A.Karshikov
(1992).
The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships.
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Protein Sci,
1,
426-471.
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PDB codes:
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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
code is
shown on the right.
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Links
