1efy
From Proteopedia
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|PDB= 1efy |SIZE=350|CAPTION= <scene name='initialview01'>1efy</scene>, resolution 2.2Å | |PDB= 1efy |SIZE=350|CAPTION= <scene name='initialview01'>1efy</scene>, resolution 2.2Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=BZC:2-(3 | + | |LIGAND= <scene name='pdbligand=BZC:2-(3'-METHOXYPHENYL) BENZIMIDAZOLE-4-CARBOXAMIDE'>BZC</scene> |
|ACTIVITY= [http://en.wikipedia.org/wiki/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30] | |ACTIVITY= [http://en.wikipedia.org/wiki/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30] | ||
|GENE= | |GENE= | ||
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[[Category: polymerase]] | [[Category: polymerase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 23 11:39:06 2008'' |
Revision as of 09:39, 23 March 2008
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| , resolution 2.2Å | |||||||
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| Ligands: | |||||||
| Activity: | NAD(+) ADP-ribosyltransferase, with EC number 2.4.2.30 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR
Overview
The nuclear enzyme poly(ADP-ribose) polymerase (PARP) facilitates the repair of DNA strand breaks and is implicated in the resistance of cancer cells to certain DNA-damaging agents. Inhibitors of PARP have clinical potential as resistance-modifying agents capable of potentiating radiotherapy and the cytotoxicity of some forms of cancer chemotherapy. The preclinical development of 2-aryl-1H-benzimidazole-4-carboxamides as resistance-modifying agents in cancer chemotherapy is described. 1H-Benzimidazole-4-carboxamides, particularly 2-aryl derivatives, are identified as a class of potent PARP inhibitors. Derivatives of 2-phenyl-1H-benzimidazole-4-carboxamide (23, K(i) = 15 nM), in which the phenyl ring contains substituents, have been synthesized. Many of these derivatives exhibit K(i) values for PARP inhibition < 10 nM, with 2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide (78, K(i) = 1.6 nM) being one of the most potent. Insight into structure-activity relationships (SAR) for 2-aryl-1H-benzimidazole-4-carboxamides has been enhanced by studying the complex formed between 2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide (44, K(i) = 6 nM) and the catalytic domain of chicken PARP. Important hydrogen-bonding and hydrophobic interactions with the protein have been identified for this inhibitor. 2-(4-Hydroxyphenyl)-1H-benzimidazole-4-carboxamide (45, K(i) = 6 nM) potentiates the cytotoxicity of both temozolomide and topotecan against A2780 cells in vitro (by 2.8- and 2.9-fold, respectively).
About this Structure
1EFY is a Single protein structure of sequence from Gallus gallus. Full crystallographic information is available from OCA.
Reference
Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase., White AW, Almassy R, Calvert AH, Curtin NJ, Griffin RJ, Hostomsky Z, Maegley K, Newell DR, Srinivasan S, Golding BT, J Med Chem. 2000 Nov 2;43(22):4084-97. PMID:11063605
Page seeded by OCA on Sun Mar 23 11:39:06 2008
Categories: Gallus gallus | NAD(+) ADP-ribosyltransferase | Single protein | Almassy, R. | Calvert, A H. | Curtin, N J. | Golding, B T. | Griffin, R J. | Hostomsky, Z. | Maegley, K. | Newell, D R. | Srinivasan, S. | White, A W. | BZC | Benzimidazole | Catalytic fragment | Crystal structure | Inhibitor | Polymerase
