1QUR

HUMAN ALPHA-THROMBIN IN COMPLEX WITH BIVALENT, BENZAMIDINE-BASED SYNTHETIC INHIBITOR

Summary for 1QUR

• Entry DOI: 10.2210/pdb1qur/pdb
• Descriptor: HUMAN THROMBIN (ALPHA CHAIN), HUMAN THROMBIN (BETA CHAIN), BIVALENT INHIBITOR (BZA-2 HIRULOG), ... (4 entities in total)
• Functional Keywords: trypsin like serine protease, blood coagulation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734 P00734
• Total number of polymer chains: 3
• Total formula weight: 35187.25

Authors

Renatus, M.,Steinmetzer, T. (deposition date: 1999-07-02, release date: 1999-10-14, Last modification date: 2024-10-30)

Primary citation

Steinmetzer, T.,Renatus, M.,Kunzel, S.,Eichinger, A.,Bode, W.,Wikstrom, P.,Hauptmann, J.,Sturzebecher, J.
Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines.
Eur.J.Biochem., 265:598-605, 1999

PubMed Abstract: Two bivalent thrombin inhibitors were synthesized, which consist of a benzamidine-based active-site-blocking segment, a fibrinogen recognition exosite inhibitor and a peptidic linker connecting these fragments. BZA-1 hirulog contains an Nalpha-(2-naphthylsulfonyl)-S-3-amidinophenylalanyl-is onipecotic acid residue connected via the carboxyl group to the linker segment. The active-site-directed moiety of BZA-2 hirulog [Nalpha-(2-naphthylsulfonyl-glutamyl)-R-4-amidinophenylal anyl-piperid ide] was coupled to the linker via the side chain of the glutamic acid. Both BZA-hirulogs contain almost identical linker-exo site inhibitor parts, except for the substitution of a glycine as the first linker residue in BZA-1 hirulog by a gamma-amino butyric acid in BZA-2 hirulog, thus increasing flexibility and linker length by two additional atoms. BZA-1 hirulog showed moderate potency (Ki = 0. 50 +/- 0.14 nM), while BZA-2 hirulog was characterized as a slow, tight binding inhibitor of thrombin (Ki = 0.29 +/- 0.08 pM). The stability in human plasma of both analogs was strongly improved compared with hirulog-1. For BZA-2 hirulog a significantly reduced plasma clearance was observed after intravenous injection in rats compared with BZA-1 hirulog and hirulog-1. The X-ray structure of the BZA-2 hirulog in complex with human alpha-thrombin was solved and confirmed the expected bivalent binding mode.

PubMed: 10504391
DOI: 10.1046/j.1432-1327.1999.00742.x

Experimental method

X-RAY DIFFRACTION (2 Å)