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1a4w
From Proteopedia
| 1a4w, resolution 1.80Å () | |||||||||
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| Sites: | |||||||||
| Ligands: | , , | ||||||||
| Non-Standard Residues: | , , | ||||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||||
| Domains: | Thrombin_light, Tryp_SPc | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
CRYSTAL STRUCTURES OF THROMBIN WITH THIAZOLE-CONTAINING INHIBITORS: PROBES OF THE S1' BINDING SITE
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.
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
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
1A4W is a 3 chains structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Matthews JH, Krishnan R, Costanzo MJ, Maryanoff BE, Tulinsky A. Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site. Biophys J. 1996 Nov;71(5):2830-9. PMID:8913620 doi:10.1016/S0006-3495(96)79479-1
Page seeded by OCA on Mon Feb 16 17:46:13 2009
