1tl8
From Proteopedia
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| - | [[Image:1tl8.gif|left|200px]] | + | [[Image:1tl8.gif|left|200px]] |
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| - | '''Human DNA topoisomerase I (70 kDa) in complex with the indenoisoquinoline AI-III-52 and covalent complex with a 22 base pair DNA duplex''' | + | {{Structure |
| + | |PDB= 1tl8 |SIZE=350|CAPTION= <scene name='initialview01'>1tl8</scene>, resolution 3.10Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=AI3:2,3-DIMETHOXY-12H-[1,3]DIOXOLO[5,6]INDENO[1,2-C]ISOQUINOLIN-6-IUM'>AI3</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] | ||
| + | |GENE= TOP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | }} | ||
| + | |||
| + | '''Human DNA topoisomerase I (70 kDa) in complex with the indenoisoquinoline AI-III-52 and covalent complex with a 22 base pair DNA duplex''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1TL8 is a [ | + | 1TL8 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TL8 OCA]. |
==Reference== | ==Reference== | ||
| - | Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis., Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M, J Med Chem. 2005 Jul 28;48(15):4803-14. PMID:[http:// | + | Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis., Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M, J Med Chem. 2005 Jul 28;48(15):4803-14. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16033260 16033260] |
[[Category: DNA topoisomerase]] | [[Category: DNA topoisomerase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
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[[Category: topoisomerase i]] | [[Category: topoisomerase i]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:19:50 2008'' |
Revision as of 12:19, 20 March 2008
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| , resolution 3.10Å | |||||||
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| Ligands: | |||||||
| Gene: | TOP1 (Homo sapiens) | ||||||
| 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 indenoisoquinoline AI-III-52 and covalent complex with a 22 base pair DNA duplex
Contents |
Overview
Several norindenoisoquinolines substituted with methoxy or methylenedioxy groups have been prepared and their anticancer properties evaluated in cancer cell cultures and in topoisomerase I inhibition assays. 2,3-Dimethoxy-8,9-methylenedioxy-11H-indeno[1,2-c]isoquinoline hydrochloride (14) is a strong topoisomerase I inhibitor and also displays very high cytotoxicity in the NCI cancer cell culture screen (mean graph midpoint of 50 nM). The X-ray crystal structure of norindenoisoquinoline 14 in complex with topoisomerase I and DNA has been solved, providing insight into the structure-activity relationships within this class of new anticancer agents. The number and position of the norindenoisoquinoline substituents have a significant influence on biological activity and demonstrate that substitution on the nitrogen atom is not an absolute requirement for the antitumor effect of the indenoisoquinolines. Removal of the 11-keto group from the lead compound 1 and replacement of the N-alkyllactam with an unsubstituted pyridine ring causes the indenoisoquinoline ring system to flip over in the DNA-enzyme-inhibitor ternary complex. This allows the nitrogen atom to assume the hydrogen bond acceptor role of the 11-keto group, resulting in hydrogen bonding to Arg364.
Disease
Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]
About this Structure
1TL8 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis., Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M, J Med Chem. 2005 Jul 28;48(15):4803-14. PMID:16033260
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