1QJ1

Novel Covalent Active Site Thrombin Inhibitors

Summary for 1QJ1

• Entry DOI: 10.2210/pdb1qj1/pdb
• Related: 1QJ6 1QJ7
• Descriptor: THROMBIN, HIRUGEN, 6-CARBAMIMIDOYL-2-[2-HYDROXY-6-(4-HYDROXY-PHENYL)-INDAN-1-YL]-HEXANOIC ACID, ... (5 entities in total)
• Functional Keywords: blood coagulation-inhibitor, proteinase, trypsin like proteinase, protease-inhibitor, 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: 35622.60

Authors

Jhoti, H.,Cleasby, A. (deposition date: 1999-06-21, release date: 2000-06-22, Last modification date: 2024-11-13)

Primary citation

Jhoti, H.,Cleasby, A.,Reid, S.,Thomas, P.,Weir, M.,Wonacott, A.
Crystal Structures of Thrombin Complexed to a Novel Series of Synthetic Inhibitors Containing a 5,5-Trans-Lactone Template
Biochemistry, 38:7969-, 1999

PubMed Abstract: The binding modes of four active site-directed, acylating inhibitors of human alpha-thrombin have been determined using X-ray crystallography. These inhibitors (GR157368, GR166081, GR167088, and GR179849) are representatives of a series utilizing a novel 5, 5-trans-lactone template to specifically acylate Ser195 of thrombin, resulting in an acyl complex. In each case the crystal structure of the complex reveals a binding mode which is consistent with the formation of a covalent bond between the ring-opened lactone of the inhibitor and residue Ser195. Improvements in potency and selectivity of these inhibitors for thrombin are rationalized on the basis of the observed protein/inhibitor interactions identified in these complexes. Occupation of the thrombin S2 and S3 pockets is shown to be directly correlated with improved binding and a degree of selectivity. The binding mode of GR179849 to thrombin is compared with the thrombin/PPACK complex [Bode, W., Turk, D., and Karshikov, A. (1992) Protein Sci. 1, 426-471] as this represents the archetypal binding mode for a thrombin inhibitor. This series of crystal structures is the first to be reported of synthetic, nonpeptidic acylating inhibitors bound to thrombin and provides details of the molecular recognition features that resulted in nanomolar potency.

PubMed: 10387040
DOI: 10.1021/BI9830359

Experimental method

X-RAY DIFFRACTION (2 Å)