1k4t

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[[Image:1k4t.gif|left|200px]]
[[Image:1k4t.gif|left|200px]]
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{{Structure
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|PDB= 1k4t |SIZE=350|CAPTION= <scene name='initialview01'>1k4t</scene>, resolution 2.10&Aring;
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The line below this paragraph, containing "STRUCTURE_1k4t", 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=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=HG:MERCURY+(II)+ION'>HG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=TGP:5&#39;-THIO-2&#39;-DEOXY-GUANOSINE+PHOSPHONIC+ACID'>TGP</scene>, <scene name='pdbligand=TTC:(S)-10-[(DIMETHYLAMINO)METHYL]-4-ETHYL-4,9-DIHYDROXY-1H-PYRANO[3&#39;,4&#39;&#58;6,7]INOLIZINO[1,2-B]-QUINOLINE-3,14(4H,12H)-DIONE'>TTC</scene>, <scene name='pdbligand=TTG:2-(1-DIMETHYLAMINOMETHYL-2-HYDROXY-8-HYDROXYMETHYL-9-OXO-9,11-DIHYDRO-INDOLIZINO[1,2-B]QUINOLIN-7-YL)-2-HYDROXY-BUTYRIC+ACID'>TTG</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=
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|DOMAIN=
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{{STRUCTURE_1k4t| PDB=1k4t | SCENE= }}
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|RELATEDENTRY=[[1a35|1A35]], [[1a31|1A31]], [[1a36|1A36]], [[1k4s|1K4S]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1k4t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1k4t OCA], [http://www.ebi.ac.uk/pdbsum/1k4t PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1k4t RCSB]</span>
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}}
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'''HUMAN DNA TOPOISOMERASE I (70 KDA) IN COMPLEX WITH THE POISON TOPOTECAN AND COVALENT COMPLEX WITH A 22 BASE PAIR DNA DUPLEX'''
'''HUMAN DNA TOPOISOMERASE I (70 KDA) IN COMPLEX WITH THE POISON TOPOTECAN AND COVALENT COMPLEX WITH A 22 BASE PAIR DNA DUPLEX'''
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[[Category: Staker, B L.]]
[[Category: Staker, B L.]]
[[Category: Stewart, L J.]]
[[Category: Stewart, L J.]]
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[[Category: complex (isomerase/dna)]]
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[[Category: Dna]]
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[[Category: dna]]
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[[Category: Drug]]
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[[Category: drug]]
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[[Category: Poison]]
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[[Category: poison]]
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[[Category: Topoisomerase i]]
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[[Category: topoisomerase i]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 22:18:25 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 21:43:27 2008''
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Revision as of 19:18, 2 May 2008

Image:1k4t.gif

Template:STRUCTURE 1k4t

HUMAN DNA TOPOISOMERASE I (70 KDA) IN COMPLEX WITH THE POISON TOPOTECAN AND COVALENT COMPLEX WITH A 22 BASE PAIR DNA DUPLEX


Overview

We report the x-ray crystal structure of human topoisomerase I covalently joined to double-stranded DNA and bound to the clinically approved anticancer agent Topotecan. Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (-1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme-substrate complex, Topotecan acts as an uncompetitive inhibitor. The structure can explain several of the known structure-activity relationships of the camptothecin family of anticancer drugs and suggests that there are at least two classes of mutations that can produce a drug-resistant enzyme. The first class includes changes to residues that contribute to direct interactions with the drug, whereas a second class would alter interactions with the DNA and thereby destabilize the drug-binding site.

About this Structure

1K4T is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

The mechanism of topoisomerase I poisoning by a camptothecin analog., Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L, Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92. Epub 2002 Nov 8. PMID:12426403 Page seeded by OCA on Fri May 2 22:18:25 2008

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OCA

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