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| - | [[Image:1g2m.jpg|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1g2m| PDB=1g2m | SCENE= }} | | {{STRUCTURE_1g2m| PDB=1g2m | SCENE= }} |
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| - | '''FACTOR XA INHIBITOR COMPLEX'''
| + | ===FACTOR XA INHIBITOR COMPLEX=== |
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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_11342132}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 11342132 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_11342132}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Inhibitor complex]] | | [[Category: Inhibitor complex]] |
| | [[Category: Serine proteinase]] | | [[Category: Serine proteinase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 17:03:35 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 04:18:58 2008'' |
Revision as of 01:18, 1 July 2008
Template:STRUCTURE 1g2m
FACTOR XA INHIBITOR COMPLEX
Template:ABSTRACT PUBMED 11342132
About this Structure
1G2M is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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 Tue Jul 1 04:18:58 2008
