1tl8: Difference between revisions
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New page: left|200px<br /> <applet load="1tl8" size="450" color="white" frame="true" align="right" spinBox="true" caption="1tl8, resolution 3.10Å" /> '''Human DNA topoisome... |
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[[Image:1tl8.gif|left|200px]]<br /> | [[Image:1tl8.gif|left|200px]]<br /><applet load="1tl8" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="1tl8" size=" | |||
caption="1tl8, resolution 3.10Å" /> | caption="1tl8, resolution 3.10Å" /> | ||
'''Human DNA topoisomerase I (70 kDa) in complex with the indenoisoquinoline AI-III-52 and covalent complex with a 22 base pair DNA duplex'''<br /> | '''Human DNA topoisomerase I (70 kDa) in complex with the indenoisoquinoline AI-III-52 and covalent complex with a 22 base pair DNA duplex'''<br /> | ||
==Overview== | ==Overview== | ||
Several norindenoisoquinolines substituted with methoxy or methylenedioxy | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1TL8 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with AI3 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http:// | 1TL8 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=AI3:'>AI3</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TL8 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Ioanoviciu, A.]] | [[Category: Ioanoviciu, A.]] | ||
[[Category: Pommier, Y.]] | [[Category: Pommier, Y.]] | ||
[[Category: Staker, B | [[Category: Staker, B L.]] | ||
[[Category: Stewart, L.]] | [[Category: Stewart, L.]] | ||
[[Category: AI3]] | [[Category: AI3]] | ||
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[[Category: topoisomerase i]] | [[Category: topoisomerase i]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:14:42 2008'' | ||
