2cn0: Difference between revisions
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[[Image:2cn0.jpg|left|200px]] | [[Image:2cn0.jpg|left|200px]] | ||
'''COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR''' | {{Structure | ||
|PDB= 2cn0 |SIZE=350|CAPTION= <scene name='initialview01'>2cn0</scene>, resolution 1.30Å | |||
|SITE= <scene name='pdbsite=AC1:Ca+Binding+Site+For+Chain+H'>AC1</scene> | |||
|LIGAND= <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=F25:4-(1R,3AS,4R,8AS,8BR)-[1-DIFLUOROMETHYL-2-(4-FLUOROBENZYL)-3-OXODECAHYDROPYRROLO[3,4-A]PYRROLIZIN-4-YL]BENZAMIDINE'>F25</scene> and <scene name='pdbligand=SIN:SUCCINIC ACID'>SIN</scene> | |||
|ACTIVITY= [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] | |||
|GENE= | |||
}} | |||
'''COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2CN0 is a [ | 2CN0 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CN0 OCA]. | ||
==Reference== | ==Reference== | ||
Mapping the fluorophilicity of a hydrophobic pocket: synthesis and biological evaluation of tricyclic thrombin inhibitors directing fluorinated alkyl groups into the p pocket., Hoffmann-Roder A, Schweizer E, Egger J, Seiler P, Obst-Sander U, Wagner B, Kansy M, Banner DW, Diederich F, ChemMedChem. 2006 Nov;1(11):1205-15. PMID:[http:// | Mapping the fluorophilicity of a hydrophobic pocket: synthesis and biological evaluation of tricyclic thrombin inhibitors directing fluorinated alkyl groups into the p pocket., Hoffmann-Roder A, Schweizer E, Egger J, Seiler P, Obst-Sander U, Wagner B, Kansy M, Banner DW, Diederich F, ChemMedChem. 2006 Nov;1(11):1205-15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17001711 17001711] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
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[[Category: serine protease inhibitor complex]] | [[Category: serine protease inhibitor complex]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:17:27 2008'' | ||
Revision as of 14:17, 20 March 2008
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| 2cn0, resolution 1.30Å | |||||||||||||
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| Sites: | AC1 | ||||||||||||
| Ligands: | NA, CA, F25 and SIN | ||||||||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR
Overview
In the completion of our fluorine scan of tricyclic inhibitors to map the fluorophilicity/fluorophobicity of the thrombin active site, a series of 11 new ligands featuring alkyl, alkenyl, and fluoroalkyl groups was prepared to explore fluorine effects on binding into the hydrophobic proximal (P) pocket, lined by Tyr 60A and Trp 60D, His 57, and Leu 99. The synthesis of the tricyclic scaffolds was based on the 1,3-dipolar cycloaddition of azomethine ylides, derived from L-proline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide. Introduction of alkyl, alkenyl, and partially fluorinated alkyl residues was achieved upon substitution of a sulfonyl group by mixed Mg/Zn organometallics followed by oxidation/deoxyfluorination, as well as oxidation/reduction/deoxyfluorination sequences. In contrast, the incorporation of perfluoroalkyl groups required a stereoselective nucleophilic addition reaction at the "upper" carbonyl group of the tricycles, thereby yielding scaffolds with an additional OH, F, or OMe group, respectively. All newly prepared inhibitors showed potent biological activity, with inhibitory constants (K(i) values) in the range of 0.008-0.163 microM. The X-ray crystal structure of a protein-ligand complex revealed the exact positioning of a difluoromethyl substituent in the tight P pocket. Fluorophilic characteristics are attributed to this hydrophobic pocket, although the potency of the inhibitors was found to be modulated by steric rather than electronic factors.
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
2CN0 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Mapping the fluorophilicity of a hydrophobic pocket: synthesis and biological evaluation of tricyclic thrombin inhibitors directing fluorinated alkyl groups into the p pocket., Hoffmann-Roder A, Schweizer E, Egger J, Seiler P, Obst-Sander U, Wagner B, Kansy M, Banner DW, Diederich F, ChemMedChem. 2006 Nov;1(11):1205-15. PMID:17001711
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