|
|
| (14 intermediate revisions by the same user not shown) |
| Line 1: |
Line 1: |
| [[Image:199d.gif|left|200px]]<br /><applet load="199d" size="450" color="white" frame="true" align="right" spinBox="true"
| |
| caption="199d" />
| |
| '''SOLUTION STRUCTURE OF THE MONOALKYLATED MITOMYCIN C-DNA COMPLEX'''<br />
| |
|
| |
|
| ==Overview== | | ==Solution structure of the monoalkylated mitomycin c-DNA complex== |
| Mitomycin C (MC) is a potent antitumor antibiotic which alkylates DNA, through covalent linkage of its C-1" position with the exocyclic N2 amino, group of guanine to yield the [MC]dG adduct at the duplex level. We report, on the solution structure of the monoalkylated MC-DNA 9-mer complex where, the [MC]dG5 adduct is positioned opposite dC14 in the, d(A3-C4-[MC]G5-T6).d(A13-C14-G15-T16) sequence context. The solution, structure was solved based on a combined NMR-molecular dynamics study, including NOE intensity based refinement. The formation of the [MC]dG, adduct occurs with retention of the Watson-Crick alignment at the, [MC]dG5.dC14 base-pair and flanking pairs in the complex. The MC ring is, positioned in the minor groove with its indoloquinone aromatic ring system, at a approximately 45 degrees angle relative to the helix axis and, directed towards the 3'-direction on the unmodified strand. The MC, indoloquinone chromophore is asymmetrically positioned in a slightly, widened minor groove so that its plane is parallel to and stacked over the, d(C14-G15-T16) segment on the unmodified strand with its other face, exposed to solvent. The MC five-membered ring adopts an envelope pucker, with its C-2" atom displaced from the mean plane and directed away from, the unmodified strand. We observe conformational perturbations in the DNA, 9-mer duplex on formation of the monoalkylated MC complex. Specifically, the base-pairs are displaced by approximately -3.0 A towards the major, groove on positioning the MC in the minor groove. This perturbation is, accompanied by base stacking patterns similar to those observed in A-DNA, while the majority of the sugars adopt puckers characteristic of B-DNA., Conformational perturbations as monitored by helix twist, sugar pucker, pseudorotation and glycosidic torsion angles are also observed for the, d(T6-C7-I8).d(C11-G12-A13) segment that is adjacent to but does not, overlap the MC binding on the 9-mer duplex. We note that the O-10" atom on, the carbamate side-chain of MC forms an intermolecular hydrogen bond with, the exocyclic amino group of dG15 in two of the three refined structures, of the complex. The solution structure of the complex containing this, intramolecular hydrogen bond readily explains both the previously observed, d(C-G).d(C-G) sequence requirement for cross-linking and the observed, somewhat less stringent, requirement of the same sequence for the initial, monoalkylation step.(ABSTRACT TRUNCATED AT 400 WORDS)
| | <StructureSection load='199d' size='340' side='right'caption='[[199d]]' scene=''> |
| | | == Structural highlights == |
| ==About this Structure== | | <table><tr><td colspan='2'>[[199d]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=199D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=199D FirstGlance]. <br> |
| 199D is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with MOC as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=199D OCA].
| | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MOC:CARBAMIC+ACID+2,6-DIAMINO-5-METHYL-4,7-DIOXO-2,3,4,7-TETRAHYDRO-1H-3A-AZA-CYCLOPENTA[A]INDEN-8-YLMETHYL+ESTER'>MOC</scene></td></tr> |
| ==Reference==
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=199d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=199d OCA], [https://pdbe.org/199d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=199d RCSB], [https://www.ebi.ac.uk/pdbsum/199d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=199d ProSAT]</span></td></tr> |
| Solution structure of the monoalkylated mitomycin C-DNA complex., Sastry M, Fiala R, Lipman R, Tomasz M, Patel DJ, J Mol Biol. 1995 Mar 24;247(2):338-59. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=7707379 7707379]
| | </table> |
| [[Category: Protein complex]] | | __TOC__ |
| [[Category: Fiala, R.]] | | </StructureSection> |
| [[Category: Lipman, R.]] | | [[Category: Large Structures]] |
| [[Category: Patel, D.J.]] | | [[Category: Fiala R]] |
| [[Category: Sastry, M.]] | | [[Category: Lipman R]] |
| [[Category: Tomasz, M.]] | | [[Category: Patel DJ]] |
| [[Category: MOC]]
| | [[Category: Sastry M]] |
| [[Category: dna]]
| | [[Category: Tomasz M]] |
| [[Category: double helix]]
| |
| [[Category: mitomycin]]
| |
| [[Category: nmr]]
| |
| | |
| ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sat Nov 24 22:14:15 2007''
| |
