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PDBsum entry 1a4w
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Hydrolase/hydrolase inhibitor
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PDB id
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1a4w
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Contents |
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* Residue conservation analysis
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Enzyme class:
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Chains L, H:
E.C.3.4.21.5
- thrombin.
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Reaction:
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Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.
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Biophys J
71:2830-2839
(1996)
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PubMed id:
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Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site.
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J.H.Matthews,
R.Krishnan,
M.J.Costanzo,
B.E.Maryanoff,
A.Tulinsky.
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ABSTRACT
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Structures of the blood clotting enzyme thrombin complexed with hirugen and two
active site inhibitors, RWJ-50353
10080(N-methyl-D-phenylalanyl-N-[5-[(aminoiminomethyl)amino]-1-
[[(2-benzothiazolyl)carbonyl]butyl]-L-prolinamide trifluoroacetate hydrate) and
RWJ-50215 (N-[4-(aminoiminomethyl)amino-1-[2-
(thiazol-2-ylcarbonylethyl)piperidin-
1-ylcarbonyl]butyl]-5-(dimethylamino)naphthalenesulfonamide trifluoroacetate
hydrate), were determined by x-ray crystallography. The refinements converged at
R values of 0.158 in the 7.0-2.3-A range for RWJ-50353 and 0.155 in the
7.0-1.8-A range for RWJ-50215. Interactions between the protein and the thiazole
rings of the two inhibitors provide new valuable information about the S1'
binding site of thrombin. The RWJ-50353 inhibitor consists of an S1'-binding
benzothiazole group linked to the D-Phe-Pro-Arg chloromethyl ketone motif.
Interactions with the S1-S3 sites are similar to the
D-phenylalanyl-prolyl-arginyl chloromethylketone structure. In RWJ-50215, a
S1'-binding 2-ketothiazole group was added to the thrombin inhibitor-like
framework of dansylarginine N-(3-ethyl-1,5-pentanediyl)amide. The geometry at
the S1-S3 sites here is also similar to that of the parent compound. The
benzothiazole and 2-ketothiazole groups bind in a cavity surrounded by His57,
Tyr60A, Trp60D, and Lys60F. This location of the S1' binding site is consistent
with previous structures of thrombin complexes with hirulog-3, CVS-995, and
hirutonin-2 and -6. The ring nitrogen of the RWJ-50353 benzothiazole forms a
hydrogen bond with His57, and Lys60F reorients because of close contacts. The
oxygen and nitrogen of the ketothiazole of RWJ-50215 hydrogen bond with the NZ
atom of Lys60F.
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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.I.Zavodszky,
A.Rohatgi,
J.R.Van Voorst,
H.Yan,
and
L.A.Kuhn
(2009).
Scoring ligand similarity in structure-based virtual screening.
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J Mol Recognit,
22,
280-292.
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J.J.Slon-Usakiewicz,
J.Sivaraman,
Y.Li,
M.Cygler,
and
Y.Konishi
(2000).
Design of P1' and P3' residues of trivalent thrombin inhibitors and their crystal structures.
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Biochemistry,
39,
2384-2391.
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PDB codes:
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R.Krishnan,
I.Mochalkin,
R.Arni,
and
A.Tulinsky
(2000).
Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1.
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Acta Crystallogr D Biol Crystallogr,
56,
294-303.
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PDB codes:
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R.Recacha,
M.J.Costanzo,
B.E.Maryanoff,
M.Carson,
L.DeLucas,
and
D.Chattopadhyay
(2000).
Structure of human alpha-thrombin complexed with RWJ-51438 at 1.7 A: unusual perturbation of the 60A-60I insertion loop.
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Acta Crystallogr D Biol Crystallogr,
56,
1395-1400.
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PDB code:
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A.Betz,
P.W.Wong,
and
U.Sinha
(1999).
Inhibition of factor Xa by a peptidyl-alpha-ketothiazole involves two steps. Evidence for a stabilizing conformational change.
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Biochemistry,
38,
14582-14591.
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R.Recacha,
M.Carson,
M.J.Costanzo,
B.Maryanoff,
L.J.DeLucas,
and
D.Chattopadhyay
(1999).
Structure of the RWJ-51084-bovine pancreatic beta-trypsin complex at 1.8 A.
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Acta Crystallogr D Biol Crystallogr,
55,
1785-1791.
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PDB code:
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K.Kamata,
H.Kawamoto,
T.Honma,
T.Iwama,
and
S.H.Kim
(1998).
Structural basis for chemical inhibition of human blood coagulation factor Xa.
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Proc Natl Acad Sci U S A,
95,
6630-6635.
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PDB codes:
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R.Krishnan,
E.Zhang,
K.Hakansson,
R.K.Arni,
A.Tulinsky,
M.S.Lim-Wilby,
O.E.Levy,
J.E.Semple,
and
T.K.Brunck
(1998).
Highly selective mechanism-based thrombin inhibitors: structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes.
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Biochemistry,
37,
12094-12103.
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PDB codes:
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S.Tada,
and
J.J.Blow
(1998).
The replication licensing system.
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Biol Chem,
379,
941-949.
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W.C.Ripka
(1997).
New thrombin inhibitors in cardiovascular disease.
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Curr Opin Chem Biol,
1,
242-253.
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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
