1efy

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[[Image:1efy.jpg|left|200px]]
[[Image:1efy.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 1efy |SIZE=350|CAPTION= <scene name='initialview01'>1efy</scene>, resolution 2.2&Aring;
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The line below this paragraph, containing "STRUCTURE_1efy", creates the "Structure Box" on the page.
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|SITE=
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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=BZC:2-(3&#39;-METHOXYPHENYL)+BENZIMIDAZOLE-4-CARBOXAMIDE'>BZC</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/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] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE=
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-->
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|DOMAIN=
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{{STRUCTURE_1efy| PDB=1efy | SCENE= }}
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|RELATEDENTRY=[[2paw|2PAW]], [[1pax|1PAX]], [[2pax|2PAX]], [[3pax|3PAX]], [[4pax|4PAX]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1efy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1efy OCA], [http://www.ebi.ac.uk/pdbsum/1efy PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1efy RCSB]</span>
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}}
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'''CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR'''
'''CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR'''
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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:[http://www.ncbi.nlm.nih.gov/pubmed/11063605 11063605]
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:[http://www.ncbi.nlm.nih.gov/pubmed/11063605 11063605]
[[Category: Gallus gallus]]
[[Category: Gallus gallus]]
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[[Category: NAD(+) ADP-ribosyltransferase]]
 
[[Category: Single protein]]
[[Category: Single protein]]
[[Category: Almassy, R.]]
[[Category: Almassy, R.]]
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[[Category: Srinivasan, S.]]
[[Category: Srinivasan, S.]]
[[Category: White, A W.]]
[[Category: White, A W.]]
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[[Category: benzimidazole]]
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[[Category: Benzimidazole]]
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[[Category: catalytic fragment]]
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[[Category: Catalytic fragment]]
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[[Category: crystal structure]]
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[[Category: Crystal structure]]
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[[Category: inhibitor]]
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[[Category: Inhibitor]]
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[[Category: polymerase]]
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[[Category: Polymerase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 15:03:03 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 20:01:45 2008''
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Revision as of 12:03, 2 May 2008

Image:1efy.jpg

Template:STRUCTURE 1efy

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 Fri May 2 15:03:03 2008

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