2c3l

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[[Image:2c3l.gif|left|200px]]<br /><applet load="2c3l" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2c3l.gif|left|200px]]
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caption="2c3l, resolution 2.35&Aring;" />
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'''IDENTIFICATION OF A BURIED POCKET FOR POTENT AND SELECTIVE INHIBITION OF CHK1: PREDICTION AND VERIFICATION'''<br />
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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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|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene>
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|LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> and <scene name='pdbligand=IDZ:3-(1H-BENZIMIDAZOL-2-YL)-1H-INDAZOLE'>IDZ</scene>
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|ACTIVITY= [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37]
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|GENE=
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}}
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'''IDENTIFICATION OF A BURIED POCKET FOR POTENT AND SELECTIVE INHIBITION OF CHK1: PREDICTION AND VERIFICATION'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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2C3L is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=IDZ:'>IDZ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Known structural/functional Site: <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C3L OCA].
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2C3L is a [[Single protein]] structure of sequence 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=2C3L OCA].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16289938 16289938]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/16289938 16289938]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: ubl conjugation]]
[[Category: ubl conjugation]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:44:33 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:10:20 2008''

Revision as of 14:10, 20 March 2008

Image:2c3l.gif


PDB ID 2c3l

Drag the structure with the mouse to rotate
, resolution 2.35Å
Sites:
Ligands: and
Activity: Transferred entry: 2.7.11.1, with EC number 2.7.1.37
Coordinates: save as pdb, mmCIF, xml



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

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