1x95

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[[Image:1x95.gif|left|200px]]
[[Image:1x95.gif|left|200px]]
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{{Structure
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|PDB= 1x95 |SIZE=350|CAPTION= <scene name='initialview01'>1x95</scene>
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The line below this paragraph, containing "STRUCTURE_1x95", creates the "Structure Box" on the page.
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|SITE=
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|LIGAND= <scene name='pdbligand=DA:2&#39;-DEOXYADENOSINE-5&#39;-MONOPHOSPHATE'>DA</scene>, <scene name='pdbligand=DC:2&#39;-DEOXYCYTIDINE-5&#39;-MONOPHOSPHATE'>DC</scene>, <scene name='pdbligand=DG:2&#39;-DEOXYGUANOSINE-5&#39;-MONOPHOSPHATE'>DG</scene>, <scene name='pdbligand=DT:THYMIDINE-5&#39;-MONOPHOSPHATE'>DT</scene>, <scene name='pdbligand=XR2:1-METHYL-9-[12-(9-METHYLPHENAZIN-10-IUM-1-YL)-12-OXO-2,11-DIAZA-5,8-DIAZONIADODEC-1-ANOYL]PHENAZIN-10-IUM'>XR2</scene>
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{{STRUCTURE_1x95| PDB=1x95 | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1x95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1x95 OCA], [http://www.ebi.ac.uk/pdbsum/1x95 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1x95 RCSB]</span>
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'''solution structure of the B-DNA hexamer ATGCAT complexed with MLN944, a bisphenazine anticancer drug'''
'''solution structure of the B-DNA hexamer ATGCAT complexed with MLN944, a bisphenazine anticancer drug'''
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==About this Structure==
==About this Structure==
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1X95 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X95 OCA].
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Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X95 OCA].
==Reference==
==Reference==
Novel DNA bis-intercalation by MLN944, a potent clinical bisphenazine anticancer drug., Dai J, Punchihewa C, Mistry P, Ooi AT, Yang D, J Biol Chem. 2004 Oct 29;279(44):46096-103. Epub 2004 Aug 17. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15317822 15317822]
Novel DNA bis-intercalation by MLN944, a potent clinical bisphenazine anticancer drug., Dai J, Punchihewa C, Mistry P, Ooi AT, Yang D, J Biol Chem. 2004 Oct 29;279(44):46096-103. Epub 2004 Aug 17. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15317822 15317822]
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[[Category: Protein complex]]
 
[[Category: Dai, J.]]
[[Category: Dai, J.]]
[[Category: Mistry, P.]]
[[Category: Mistry, P.]]
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[[Category: Punchihewa, C.]]
[[Category: Punchihewa, C.]]
[[Category: Yang, D.]]
[[Category: Yang, D.]]
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[[Category: anticancer drug]]
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[[Category: Anticancer drug]]
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[[Category: ap-1]]
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[[Category: Ap-1]]
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[[Category: mln944]]
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[[Category: Mln944]]
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[[Category: nmr]]
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[[Category: Nmr]]
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[[Category: novel dna binding]]
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[[Category: Novel dna binding]]
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[[Category: structure]]
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[[Category: Structure]]
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[[Category: transcription inhibition]]
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[[Category: Transcription inhibition]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 14:43:34 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:46:26 2008''
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Revision as of 11:43, 3 May 2008

Image:1x95.gif

Template:STRUCTURE 1x95

solution structure of the B-DNA hexamer ATGCAT complexed with MLN944, a bisphenazine anticancer drug


Overview

The new bisphenazine anticancer drug MLN944 is a novel cytotoxic agent with exceptional anti-tumor activity against a range of human and murine tumor models both in vitro and in vivo. MLN944 has recently entered Phase I clinical trials. Despite the structural similarity with its parent monophenazine carboxamide and acridine carboxamide anticancer compounds, MLN944 appears to work by a distinct mechanism of inhibiting DNA transcription rather than the expected mechanism of topoisomerase I and II inhibition. Here we present the first NMR structure of MLN944 complexed with d(ATGCAT)(2) DNA duplex, demonstrating a novel binding mode in which the two phenazine rings bis-intercalate at the 5'-TpG site, with the carboxamide amino linker lying in the major groove of DNA. The MLN944 molecule adopts a significantly unexpected conformation and side chain orientation in the DNA complex, with the N10 on the phenazine ring protonated at pH 7. The phenazine chromophore of MLN944 is very well stacked with the flanking DNA base pairs using the parallel base-stacking intercalation binding mode. The DNA sequence specificity and the groove recognition of MLN944 binding is determined by several site-specific hydrogen bond interactions with the central G:C base pair as well as the favorable stacking interactions with the 5'-flanking thymine. The specific binding site of MLN944 is known to be recognized by a number of important transcription factors. Our electrophoretic gel mobility shift assay results demonstrated that the c-Jun DNA binding to the AP-1 site is significantly inhibited by MLN944 in a dose-dependent manner. Thus, the exceptional biological activity of MLN944 may be due to its novel DNA binding mode leading to a unique mechanism of action.

About this Structure

Full crystallographic information is available from OCA.

Reference

Novel DNA bis-intercalation by MLN944, a potent clinical bisphenazine anticancer drug., Dai J, Punchihewa C, Mistry P, Ooi AT, Yang D, J Biol Chem. 2004 Oct 29;279(44):46096-103. Epub 2004 Aug 17. PMID:15317822 Page seeded by OCA on Sat May 3 14:43:34 2008

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