1nh3

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[[Image:1nh3.gif|left|200px]]
[[Image:1nh3.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 1nh3 |SIZE=350|CAPTION= <scene name='initialview01'>1nh3</scene>, resolution 3.10&Aring;
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The line below this paragraph, containing "STRUCTURE_1nh3", 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=CAR:CYTOSINE+ARABINOSE-5&#39;-PHOSPHATE'>CAR</scene>, <scene name='pdbligand=DA:2&#39;-DEOXYADENOSINE-5&#39;-MONOPHOSPHATE'>DA</scene>, <scene name='pdbligand=DC:2&#39;-DEOXYCYTIDINE-5&#39;-MONOPHOSPHATE'>DC</scene>, <scene name='pdbligand=DG:2&#39;-DEOXYGUANOSINE-5&#39;-MONOPHOSPHATE'>DG</scene>, <scene name='pdbligand=DT:THYMIDINE-5&#39;-MONOPHOSPHATE'>DT</scene>, <scene name='pdbligand=DU:2&#39;-DEOXYURIDINE-5&#39;-MONOPHOSPHATE'>DU</scene>, <scene name='pdbligand=GNG:2&#39;-DEOXY-GUANOSINE'>GNG</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=UBB:2&#39;,3&#39;-DIDEOXY-URIDINE-5&#39;-MONOPHOSPHATE'>UBB</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/DNA_topoisomerase DNA topoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.2 5.99.1.2] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE= TOP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_1nh3| PDB=1nh3 | SCENE= }}
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|RELATEDENTRY=[[1a31|1A31]], [[1ej9|1EJ9]], [[1lpq|1LPQ]], [[1k4t|1K4T]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1nh3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nh3 OCA], [http://www.ebi.ac.uk/pdbsum/1nh3 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1nh3 RCSB]</span>
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}}
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'''Human Topoisomerase I Ara-C Complex'''
'''Human Topoisomerase I Ara-C Complex'''
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[[Category: Redinbo, M R.]]
[[Category: Redinbo, M R.]]
[[Category: Stewart, L.]]
[[Category: Stewart, L.]]
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[[Category: ara-c]]
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[[Category: Ara-c]]
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[[Category: dna damage]]
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[[Category: Dna damage]]
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[[Category: isomerase]]
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[[Category: Isomerase]]
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[[Category: protein-dna complex]]
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[[Category: Protein-dna complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:31:22 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:30:20 2008''
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Revision as of 23:31, 2 May 2008

Image:1nh3.gif

Template:STRUCTURE 1nh3

Human Topoisomerase I Ara-C Complex


Contents

Overview

1-beta-d-Arabinofuranosylcytosine (Ara-C) is a potent antineoplastic drug used in the treatment of acute leukemia. Previous biochemical studies indicated the incorporation of Ara-C into DNA reduced the catalytic activity of human topoisomerase I by decreasing the rate of single DNA strand religation by the enzyme by 2-3-fold. We present the 3.1 A crystal structure of human topoisomerase I in covalent complex with an oligonucleotide containing Ara-C at the +1 position of the non-scissile DNA strand. The structure reveals that a hydrogen bond formed between the 2'-hydroxyl of Ara-C and the O4' of the adjacent -1 base 5' to the damage site stabilizes a C3'-endo pucker in the Ara-C arabinose ring. The structural distortions at the site of damage are translated across the DNA double helix to the active site of human topoisomerase I. The free sulfhydryl at the 5'-end of the nicked DNA strand in this trapped covalent complex is shifted out of alignment with the 3'-phosphotyrosine linkage at the catalytic tyrosine 723 residue, producing a geometry not optimal for religation. The subtle structural changes caused by the presence of Ara-C in the DNA duplex may contribute to the cytotoxicity of this leukemia drug by prolonging the lifetime of the covalent human topoisomerase I-DNA complex.

Disease

Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]

About this Structure

1NH3 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural impact of the leukemia drug 1-beta-D-arabinofuranosylcytosine (Ara-C) on the covalent human topoisomerase I-DNA complex., Chrencik JE, Burgin AB, Pommier Y, Stewart L, Redinbo MR, J Biol Chem. 2003 Apr 4;278(14):12461-6. Epub 2003 Jan 17. PMID:12533542 Page seeded by OCA on Sat May 3 02:31:22 2008

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OCA

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