1x95

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(New page: 200px<br /><applet load="1x95" size="450" color="white" frame="true" align="right" spinBox="true" caption="1x95" /> '''solution structure of the B-DNA hexamer ATGC...)
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[[Image:1x95.gif|left|200px]]<br /><applet load="1x95" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1x95" />
 
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'''solution structure of the B-DNA hexamer ATGCAT complexed with MLN944, a bisphenazine anticancer drug'''<br />
 
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==Overview==
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==Solution structure of the DNA-hexamer ATGCAT complexed with DNA Bis-intercalating Anticancer Drug XR5944 (MLN944)==
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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.
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<StructureSection load='1x95' size='340' side='right'caption='[[1x95]]' scene=''>
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== Structural highlights ==
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==About this Structure==
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<table><tr><td colspan='2'>[[1x95]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X95 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1X95 FirstGlance]. <br>
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1X95 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with XR2 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1X95 OCA].
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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></td></tr>
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==Reference==
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1x95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1x95 OCA], [https://pdbe.org/1x95 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1x95 RCSB], [https://www.ebi.ac.uk/pdbsum/1x95 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1x95 ProSAT]</span></td></tr>
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=15317822 15317822]
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</table>
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[[Category: Protein complex]]
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__TOC__
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[[Category: Dai, J.]]
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</StructureSection>
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[[Category: Mistry, P.]]
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[[Category: Large Structures]]
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[[Category: Ooi, A.T.]]
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[[Category: Dai J]]
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[[Category: Punchihewa, C.]]
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[[Category: Mistry P]]
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[[Category: Yang, D.]]
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[[Category: Ooi AT]]
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[[Category: XR2]]
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[[Category: Punchihewa C]]
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[[Category: anticancer drug]]
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[[Category: Yang D]]
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[[Category: ap-1]]
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[[Category: mln944]]
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[[Category: nmr]]
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[[Category: novel dna binding]]
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[[Category: structure]]
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[[Category: transcription inhibition]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 25 01:40:22 2007''
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Current revision

Solution structure of the DNA-hexamer ATGCAT complexed with DNA Bis-intercalating Anticancer Drug XR5944 (MLN944)

PDB ID 1x95

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