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| | {{STRUCTURE_1cx3| PDB=1cx3 | SCENE= }} | | {{STRUCTURE_1cx3| PDB=1cx3 | SCENE= }} |
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| - | '''SOLUTION STRUCTURE OF A COMPLEX BETWEEN D(ATGCAT)2 AND THE ANTITUMOR BISNAPHTHALIMIDE LU-79553'''
| + | ===SOLUTION STRUCTURE OF A COMPLEX BETWEEN D(ATGCAT)2 AND THE ANTITUMOR BISNAPHTHALIMIDE LU-79553=== |
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| - | ==Overview==
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| - | Using a combination of nuclear magnetic resonance (NMR) spectroscopy experiments and molecular dynamics, we have analyzed the structure and dynamics of a complex between the bisnaphthalimide drug LU-79553 and the DNA duplex d(ATGCAT)(2). LU-79553 is a DNA-binding topoisomerase II inhibitor that is particularly effective against human solid tumors that are refractory to other drugs. We have found that the two naphthalimide chromophores of the drug bisintercalate at the TpG and CpA steps of the DNA hexanucleotide, stacking mainly with the purine G and A bases from opposite strands. The 3, 7-diazanonylene linker lies in the major groove of the DNA molecule, with its two amino groups hydrogen-bonded to the symmetry-related guanine bases. Unexpectedly, we have detected an unprecedented exchange process between two equivalent and intercalated states of the naphthalimide rings in the drug-DNA complex. The interconversion process takes place by rotational ring flipping, has an activation energy of 22 kcal mol(-)(1) for the two rings, and does not affect the aminoalkyl linker region of the drug. The exchange rate is intermediate to fast on the chemical shift time scale at 36 degrees C (1800 s(-)(1)) but slow at 2 degrees C (20 s(-)(1)). We have also observed limited flexibility for the drug linker on the picosecond time scale on the basis of NMR data and a time-averaged restrained molecular dynamics simulation. The implications of the structural and dynamic features of the DNA-LU-79553 complex on the binding specificity and on the antitumor activity of bisnaphthalimide agents are discussed.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10563793}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10563793 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10563793}} |
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| | ==About this Structure== | | ==About this Structure== |
| - | Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CX3 OCA]. | + | Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CX3 OCA]. |
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| | ==Reference== | | ==Reference== |
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| | [[Category: Naphthalimide]] | | [[Category: Naphthalimide]] |
| | [[Category: Topoisomerase]] | | [[Category: Topoisomerase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 13:12:22 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 21:41:05 2008'' |
Revision as of 18:41, 30 June 2008
Template:STRUCTURE 1cx3
SOLUTION STRUCTURE OF A COMPLEX BETWEEN D(ATGCAT)2 AND THE ANTITUMOR BISNAPHTHALIMIDE LU-79553
Template:ABSTRACT PUBMED 10563793
About this Structure
Full experimental information is available from OCA.
Reference
Solution structure and dynamics of a complex between DNA and the antitumor bisnaphthalimide LU-79553: intercalated ring flipping on the millisecond time scale., Gallego J, Reid BR, Biochemistry. 1999 Nov 16;38(46):15104-15. PMID:10563793
Page seeded by OCA on Mon Jun 30 21:41:05 2008
