1qj7
From Proteopedia
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| - | [[Image:1qj7.gif|left|200px]]<br /> | + | [[Image:1qj7.gif|left|200px]]<br /><applet load="1qj7" size="450" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1qj7" size="450" color="white" frame="true" align="right" spinBox="true" | + | |
caption="1qj7, resolution 2.2Å" /> | caption="1qj7, resolution 2.2Å" /> | ||
'''NOVEL COVALENT ACTIVE SITE THROMBIN INHIBITORS'''<br /> | '''NOVEL COVALENT ACTIVE SITE THROMBIN INHIBITORS'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1QJ7 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with GR1 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] | + | 1QJ7 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with GR1 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] Known structural/functional Site: <scene name='pdbsite=CAT:Catalytic Triad Of SER Proteinases'>CAT</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1QJ7 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: trypsin like proteinase]] | [[Category: trypsin like proteinase]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 17:53:39 2007'' |
Revision as of 15:43, 18 December 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 Known structural/functional Site: . 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
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