2cn0

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[[Image:2cn0.jpg|left|200px]]
[[Image:2cn0.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 2cn0 |SIZE=350|CAPTION= <scene name='initialview01'>2cn0</scene>, resolution 1.30&Aring;
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The line below this paragraph, containing "STRUCTURE_2cn0", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:Ca+Binding+Site+For+Chain+H'>AC1</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <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>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SIN:SUCCINIC+ACID'>SIN</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[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] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE=
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|DOMAIN=
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{{STRUCTURE_2cn0| PDB=2cn0 | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2cn0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cn0 OCA], [http://www.ebi.ac.uk/pdbsum/2cn0 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2cn0 RCSB]</span>
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}}
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'''COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR'''
'''COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR'''
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[[Category: Seiler, P.]]
[[Category: Seiler, P.]]
[[Category: Wagner, B.]]
[[Category: Wagner, B.]]
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[[Category: acute phase]]
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[[Category: Acute phase]]
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[[Category: blood coagulation]]
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[[Category: Blood coagulation]]
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[[Category: calcium-binding]]
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[[Category: Calcium-binding]]
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[[Category: glycoprotein]]
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[[Category: Glycoprotein]]
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[[Category: hydrolase]]
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[[Category: Hydrolase]]
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[[Category: serine protease]]
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[[Category: Serine protease]]
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[[Category: serine protease inhibitor complex]]
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[[Category: Serine protease inhibitor complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 22:33:06 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:23:48 2008''
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Revision as of 19:33, 3 May 2008

Image:2cn0.jpg

Template:STRUCTURE 2cn0

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.

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 Page seeded by OCA on Sat May 3 22:33:06 2008

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