1k4t

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|PDB= 1k4t |SIZE=350|CAPTION= <scene name='initialview01'>1k4t</scene>, resolution 2.10&Aring;
|PDB= 1k4t |SIZE=350|CAPTION= <scene name='initialview01'>1k4t</scene>, resolution 2.10&Aring;
|SITE=
|SITE=
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|LIGAND= <scene name='pdbligand=TTC:(S)-10-[(DIMETHYLAMINO)METHYL]-4-ETHYL-4,9-DIHYDROXY-1H-PYRANO[3',4':6,7]INOLIZINO[1,2-B]-QUINOLINE-3,14(4H,12H)-DIONE'>TTC</scene>, <scene name='pdbligand=HG:MERCURY+(II)+ION'>HG</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> and <scene name='pdbligand=PG4:TETRAETHYLENE GLYCOL'>PG4</scene>
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|LIGAND= <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=HG:MERCURY+(II)+ION'>HG</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> and <scene name='pdbligand=PG4:TETRAETHYLENE GLYCOL'>PG4</scene>
|ACTIVITY= [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]
|ACTIVITY= [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]
|GENE=
|GENE=
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[[Category: topoisomerase i]]
[[Category: topoisomerase i]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:12:36 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 23 12:26:21 2008''

Revision as of 10:26, 23 March 2008

Image:1k4t.gif


PDB ID 1k4t

Drag the structure with the mouse to rotate
, resolution 2.10Å
Ligands: , , and
Activity: DNA topoisomerase, with EC number 5.99.1.2
Coordinates: save as pdb, mmCIF, xml



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


Contents

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.

Disease

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

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

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