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1a4w
From Proteopedia
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==Overview== | ==Overview== | ||
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. | 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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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: complex (serine protease/inhibitors)]] | [[Category: complex (serine protease/inhibitors)]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 15:55:43 2007'' |
Revision as of 13:49, 12 November 2007
|
CRYSTAL STRUCTURES OF THROMBIN WITH THIAZOLE-CONTAINING INHIBITORS: PROBES OF THE S1' BINDING SITE
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1A4W is a Protein complex structure of sequences from Homo sapiens with NA, ANS and KTH as ligands. Active as Thrombin, with EC number 3.4.21.5 Structure known Active Site: CAT. Full crystallographic information is available from OCA.
Reference
Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site., Matthews JH, Krishnan R, Costanzo MJ, Maryanoff BE, Tulinsky A, Biophys J. 1996 Nov;71(5):2830-9. PMID:8913620
Page seeded by OCA on Mon Nov 12 15:55:43 2007
