1tl8
From Proteopedia
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|PDB= 1tl8 |SIZE=350|CAPTION= <scene name='initialview01'>1tl8</scene>, resolution 3.10Å | |PDB= 1tl8 |SIZE=350|CAPTION= <scene name='initialview01'>1tl8</scene>, resolution 3.10Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=AI3:2,3-DIMETHOXY-12H-[1,3]DIOXOLO[5,6]INDENO[1,2-C]ISOQUINOLIN-6-IUM'>AI3</scene> | + | |LIGAND= <scene name='pdbligand=AI3:2,3-DIMETHOXY-12H-[1,3]DIOXOLO[5,6]INDENO[1,2-C]ISOQUINOLIN-6-IUM'>AI3</scene>, <scene name='pdbligand=DA:2'-DEOXYADENOSINE-5'-MONOPHOSPHATE'>DA</scene>, <scene name='pdbligand=DC:2'-DEOXYCYTIDINE-5'-MONOPHOSPHATE'>DC</scene>, <scene name='pdbligand=DG:2'-DEOXYGUANOSINE-5'-MONOPHOSPHATE'>DG</scene>, <scene name='pdbligand=DT:THYMIDINE-5'-MONOPHOSPHATE'>DT</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=TPC:5'-THIO-2'-DEOXY-CYTOSINE+PHOSPHONIC+ACID'>TPC</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= <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> |
|GENE= TOP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= TOP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1k4t|1K4t]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1tl8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tl8 OCA], [http://www.ebi.ac.uk/pdbsum/1tl8 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1tl8 RCSB]</span> | ||
}} | }} | ||
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[[Category: Staker, B L.]] | [[Category: Staker, B L.]] | ||
[[Category: Stewart, L.]] | [[Category: Stewart, L.]] | ||
| - | [[Category: AI3]] | ||
[[Category: complex (isomerase/dna)]] | [[Category: complex (isomerase/dna)]] | ||
[[Category: dna]] | [[Category: dna]] | ||
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[[Category: topoisomerase i]] | [[Category: topoisomerase i]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:57:37 2008'' |
Revision as of 20:57, 30 March 2008
| |||||||
| , resolution 3.10Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , , , , | ||||||
| Gene: | TOP1 (Homo sapiens) | ||||||
| Activity: | DNA topoisomerase, with EC number 5.99.1.2 | ||||||
| Related: | 1K4t
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| 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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