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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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References listed in PDB file
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Key reference
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Title
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Crystal structures of thrombin with thiazole-Containing inhibitors: probes of the s1' Binding site.
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Authors
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J.H.Matthews,
R.Krishnan,
M.J.Costanzo,
B.E.Maryanoff,
A.Tulinsky.
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Ref.
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Biophys J, 1996,
71,
2830-2839.
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PubMed id
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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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Secondary reference #1
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Title
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The isomorphous structures of prethrombin2, Hirugen-, And ppack-Thrombin: changes accompanying activation and exosite binding to thrombin.
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Authors
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J.Vijayalakshmi,
K.P.Padmanabhan,
K.G.Mann,
A.Tulinsky.
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Ref.
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Protein Sci, 1994,
3,
2254-2271.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Active site and exosite binding of alpha-Thrombin.
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Authors
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A.Tulinsky,
X.Qiu.
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Ref.
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Blood Coagul Fibrinolysis, 1993,
4,
305-312.
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PubMed id
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Secondary reference #3
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Title
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Structure of the hirulog 3-Thrombin complex and nature of the s' Subsites of substrates and inhibitors.
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Authors
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X.Qiu,
K.P.Padmanabhan,
V.E.Carperos,
A.Tulinsky,
T.Kline,
J.M.Maraganore,
J.W.Fenton.
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Ref.
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Biochemistry, 1992,
31,
11689-11697.
[DOI no: ]
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PubMed id
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