1fyy
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(New page: 200px<br /><applet load="1fyy" size="450" color="white" frame="true" align="right" spinBox="true" caption="1fyy" /> '''HPRT GENE MUTATION HOTSPOT WITH A BPDE2(10R)...)
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Revision as of 22:25, 24 November 2007
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HPRT GENE MUTATION HOTSPOT WITH A BPDE2(10R) ADDUCT
Overview
2D NMR has been used to examine the structure and dynamics of a 12-mer DNA, duplex, d(T(1)A(2)G(3)T(4)C(5)A(6)A(7)G(8)G(9)G(10)C(11)A(12))-d(T(13)G(14)C(, 15)C(16)C(17)T(18)T(19)G(20)A(21)C(22)T(23)A(24)), containing a 10R adduct, at dA(7) that corresponds to trans addition of the N(6)-amino group of, dA(7) to (-)-(7S,8R,9R,10S)-7,8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(-)-(S,R,R,S)-BP DE-2]. This, DNA duplex contains the base sequence for the major dA mutational hot spot, in the HPRT gene when Chinese hamster V79 cells are given low doses of the, highly carcinogenic (+)-(R,S,S,R)-BP DE-2 enantiomer. NOE data indicate, that the hydrocarbon is intercalated on the 5'-side of the modified base, as has been seen previously for other oligonucleotides containing BP DE-2, (10R)-dA adducts. 2D chemical exchange-only experiments indicate dynamic, behavior near the intercalation site especially at the 10R adducted dA, such that this base interconverts between the normal anti conformation and, a less populated syn conformation. Ab initio molecular orbital chemical, shift calculations of nucleotide and dinucleotide fragments in the syn and, anti conformations support these conclusions. Although this DNA duplex, containing a 10R dA adduct exhibits conformational flexibility as, described, it is nevertheless more conformationally stable than the, corresponding 10S adducted duplex corresponding to trans opening of the, carcinogenic isomer (+)-(R,S,S, R)-BP DE-2, which was too dynamic to, permit NMR structure determination. UV and imino proton NMR spectral, observations indicated pronounced differences between these two, diastereomeric 12-mer duplexes, consistent with conformational disorder at, the adduct site and/or an equilibrium with a nonintercalated orientation, of the hydrocarbon in the duplex containing the 10S adduct. The existence, of conformational flexibility around adducts may be related to the, occurrence of multiple mutagenic outcomes resulting from a single DE, adduct.
About this Structure
1FYY is a Protein complex structure of sequences from [1] with BAP as ligand. Full crystallographic information is available from OCA.
Reference
NMR evidence for syn-anti interconversion of a trans opened (10R)-dA adduct of benzo[a]pyrene (7S,8R)-diol (9R,10S)-epoxide in a DNA duplex., Volk DE, Rice JS, Luxon BA, Yeh HJ, Liang C, Xie G, Sayer JM, Jerina DM, Gorenstein DG, Biochemistry. 2000 Nov 21;39(46):14040-53. PMID:11087351[[Category: benzo[a]pyrene]]
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