2cn0

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
-
[[Image:2cn0.jpg|left|200px]]<br /><applet load="2cn0" size="350" color="white" frame="true" align="right" spinBox="true"
+
[[Image:2cn0.jpg|left|200px]]
-
caption="2cn0, resolution 1.30&Aring;" />
+
 
-
'''COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR'''<br />
+
{{Structure
 +
|PDB= 2cn0 |SIZE=350|CAPTION= <scene name='initialview01'>2cn0</scene>, resolution 1.30&Aring;
 +
|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==
Line 10: Line 19:
==About this Structure==
==About this Structure==
-
2CN0 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NA:'>NA</scene>, <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=F25:'>F25</scene> and <scene name='pdbligand=SIN:'>SIN</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=AC1:Ca+Binding+Site+For+Chain+H'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CN0 OCA].
+
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://ispc.weizmann.ac.il//pmbin/getpm?pmid=17001711 17001711]
+
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]]
Line 38: Line 47:
[[Category: serine protease inhibitor complex]]
[[Category: serine protease inhibitor complex]]
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:50:21 2008''
+
''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

Image:2cn0.jpg


PDB ID 2cn0

Drag the structure with the mouse to rotate
, resolution 1.30Å
Sites:
Ligands: , , and
Activity: Thrombin, with EC number 3.4.21.5
Coordinates: save as pdb, mmCIF, xml



COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR


Contents

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

Page seeded by OCA on Thu Mar 20 16:17:27 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2cn0"
Personal tools