2c3l

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[[Image:2c3l.gif|left|200px]]
[[Image:2c3l.gif|left|200px]]
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{{Structure
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|PDB= 2c3l |SIZE=350|CAPTION= <scene name='initialview01'>2c3l</scene>, resolution 2.35&Aring;
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The line below this paragraph, containing "STRUCTURE_2c3l", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>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=IDZ:3-(1H-BENZIMIDAZOL-2-YL)-1H-INDAZOLE'>IDZ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span>
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|DOMAIN=
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{{STRUCTURE_2c3l| PDB=2c3l | 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=2c3l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c3l OCA], [http://www.ebi.ac.uk/pdbsum/2c3l PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2c3l RCSB]</span>
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}}
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'''IDENTIFICATION OF A BURIED POCKET FOR POTENT AND SELECTIVE INHIBITION OF CHK1: PREDICTION AND VERIFICATION'''
'''IDENTIFICATION OF A BURIED POCKET FOR POTENT AND SELECTIVE INHIBITION OF CHK1: PREDICTION AND VERIFICATION'''
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[[Category: Kierstan, P.]]
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[[Category: Atp-binding]]
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[[Category: Cell cycle]]
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[[Category: dna damage]]
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[[Category: Dna damage]]
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[[Category: dna repair]]
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[[Category: Dna repair]]
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[[Category: Kinase]]
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[[Category: serine/threonine-protein kinase]]
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[[Category: Serine/threonine-protein kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 21:11:56 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:15:46 2008''
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Revision as of 18:11, 3 May 2008

Image:2c3l.gif

Template:STRUCTURE 2c3l

IDENTIFICATION OF A BURIED POCKET FOR POTENT AND SELECTIVE INHIBITION OF CHK1: PREDICTION AND VERIFICATION


Overview

Inhibition of the Chk1 kinase by small molecules binding to its active site is a strategy of great therapeutic interest for oncology. We report how computational modelling predicted the binding mode of ligands of special interest to the Chk1 ATP site, for representatives of an indazole series and debromohymenialdisine. These binding modes were subsequently confirmed by X-ray crystallography. The binding mode of a potent indazole derivative involves non-conventional C-H...O and N-H...pi-aromatic interactions with the protein. These interactions are formed in a buried pocket at the periphery of the ATP-binding site, the importance of which has previously been overlooked for ligand design against Chk1. It is demonstrated that filling this pocket can confer ligands with dramatically enhanced affinity for Chk1. Structural arguments in conjunction with assay data explain why targeting this pocket is also advantageous for selective binding to Chk1. Structural overlays of known inhibitors complexed with Chk1 show that only the indazole series utilizes the pocket of interest. Therefore, the analysis presented here should prove helpful in guiding future structure-based ligand design efforts against Chk1.

About this Structure

2C3L is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Identification of a buried pocket for potent and selective inhibition of Chk1: prediction and verification., Foloppe N, Fisher LM, Francis G, Howes R, Kierstan P, Potter A, Bioorg Med Chem. 2006 Mar 15;14(6):1792-804. Epub 2005 Nov 9. PMID:16289938 Page seeded by OCA on Sat May 3 21:11:56 2008

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