2c3l
From Proteopedia
| Line 4: | Line 4: | ||
|PDB= 2c3l |SIZE=350|CAPTION= <scene name='initialview01'>2c3l</scene>, resolution 2.35Å | |PDB= 2c3l |SIZE=350|CAPTION= <scene name='initialview01'>2c3l</scene>, resolution 2.35Å | ||
|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene> | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=IDZ:3-(1H-BENZIMIDAZOL-2-YL)-1H-INDAZOLE'>IDZ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/ | + | |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> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |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> | ||
}} | }} | ||
| Line 21: | Line 24: | ||
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] | 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: Non-specific serine/threonine protein kinase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Transferred entry: 2 7.11 1]] | ||
[[Category: Fisher, L M.]] | [[Category: Fisher, L M.]] | ||
[[Category: Foloppe, N.]] | [[Category: Foloppe, N.]] | ||
| Line 29: | Line 32: | ||
[[Category: Kierstan, P.]] | [[Category: Kierstan, P.]] | ||
[[Category: Potter, A.]] | [[Category: Potter, A.]] | ||
| - | [[Category: IDZ]] | ||
| - | [[Category: SO4]] | ||
[[Category: atp-binding]] | [[Category: atp-binding]] | ||
[[Category: cell cycle]] | [[Category: cell cycle]] | ||
| Line 48: | Line 49: | ||
[[Category: ubl conjugation]] | [[Category: ubl conjugation]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:15:46 2008'' |
Revision as of 23:15, 30 March 2008
| |||||||
| , resolution 2.35Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , | ||||||
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| 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
Page seeded by OCA on Mon Mar 31 02:15:46 2008
Categories: Homo sapiens | Non-specific serine/threonine protein kinase | Single protein | Fisher, L M. | Foloppe, N. | Francis, G. | Howes, R. | Kierstan, P. | Potter, A. | Atp-binding | Cell cycle | Dna damage | Dna repair | Drug design | Kinase | Molecular modeling | Molecular recognition | Nuclear protein | Nucleotide-binding | Oncology | Phosphorylation | Polymorphism | Serine/threonine-protein kinase | Transferase | Ubl conjugation
