1qj7
From Proteopedia
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==Overview== | ==Overview== | ||
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. | 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. | ||
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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: trypsin like proteinase]] | [[Category: trypsin like proteinase]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:53:47 2007'' |
Revision as of 16:47, 12 November 2007
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NOVEL COVALENT ACTIVE SITE THROMBIN INHIBITORS
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1QJ7 is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with GR1 as ligand. Active as Thrombin, with EC number 3.4.21.5 Structure known Active Site: CAT. Full crystallographic information is available from OCA.
Reference
Crystal structures of thrombin complexed to a novel series of synthetic inhibitors containing a 5,5-trans-lactone template., Jhoti H, Cleasby A, Reid S, Thomas PJ, Weir M, Wonacott A, Biochemistry. 1999 Jun 22;38(25):7969-77. PMID:10387040
Page seeded by OCA on Mon Nov 12 18:53:47 2007
