1g30
THROMBIN INHIBITOR COMPLEX
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OverviewOverview
BACKGROUND: A major current focus of pharmaceutical research is the, development of selective inhibitors of the blood coagulation enzymes, thrombin or factor Xa to be used as orally bioavailable anticoagulant, drugs in thromboembolic disorders and in the prevention of venous and, arterial thrombosis. Simultaneous direct inhibition of thrombin and factor, Xa by synthetic proteinase inhibitors as a novel approach to, antithrombotic therapy could result in potent anticoagulants with improved, pharmacological properties. RESULTS: The binding mode of such dual, specific inhibitors of thrombin and factor Xa was determined for the first, time by comparative crystallography using human alpha-thrombin, human, des-Gla (1--44) factor Xa and bovine trypsin as the ligand receptors. The, benzamidine-based inhibitors utilize two different conformations for the, interaction with thrombin and factor Xa/trypsin, which are evoked by the, steric requirements of the topologically different S2 subsites of the, enzymes. Compared to the unliganded forms of the proteinases, ligand, binding induces conformational adjustments of thrombin and factor Xa, active site residues indicative of a pronounced induced fit mechanism., CONCLUSION: The structural data reveal the molecular basis for a desired, unselective inhibition of the two key components of the blood coagulation, cascade. The 4-(1-methyl-benzimidazole-2-yl)-methylamino-benzamidine, moieties of the inhibitors are able to fill both the small solvent, accessible as well as the larger hydrophobic S2 pockets of factor Xa and, thrombin, respectively. Distal fragments of the inhibitors are identified, which fit into both the cation hole/aromatic box of factor Xa and the, hydrophobic aryl binding site of thrombin. Thus, binding constants in the, medium-to-low nanomolar range are obtained against both enzymes.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1G30 is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with T87 as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for inhibition promiscuity of dual specific thrombin and factor Xa blood coagulation inhibitors., Nar H, Bauer M, Schmid A, Stassen JM, Wienen W, Priepke HW, Kauffmann IK, Ries UJ, Hauel NH, Structure. 2001 Jan 10;9(1):29-37. PMID:11342132
Page seeded by OCA on Mon Nov 12 16:59:59 2007