2hmd

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Stereochemistry Modulates Stability of Reduced Inter-Strand Cross-Links Arising From R- and S-alpha-methyl-gamma-OH-1,N2-propano-2'-Deoxyguanine in the 5'-CpG-3' DNA Sequence

Overview

The solution structures of, 5'-Cp-N2-dG-3'-R-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' and, 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' interstrand DNA, cross-links in the 5'-CpG-3' sequence were determined by NMR spectroscopy., These were utilized as chemically stable surrogates for the corresponding, carbinolamine interstrand cross-links arising from the crotonaldehyde- and, acetaldehyde-derived R- and, S-alpha-CH3-gamma-OH-1,N2-propanodeoxyguanosine adducts. The results, provide an explanation for the observation that interstrand cross-link, formation in the 5'-CpG-3' sequence by the R- and, S-alpha-CH3-gamma-OH-1,N2-propanodeoxyguanosine adducts is dependent upon, stereochemistry, favoring the, R-alpha-CH3-gamma-OH-1,N2-propanodeoxyguanosine adduct [Kozekov, I. D., Nechev, L. V., Moseley, M. S., Harris, C. M., Rizzo, C. J., Stone, M. P., and Harris, T. M. (2003) J. Am. Chem. Soc. 125, 50-61]. Molecular dynamics, calculations, restrained by NOE-based distances and empirical restraints, revealed that both the 5'-Cp-N2-dG-3'-R-(alpha)-CH3-propyl-5'-Cp-N2-dG-3', and 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' cross-links were, located in the minor groove and retained Watson-Crick hydrogen bonds at, the tandem cross-linked C.G base pairs. However, for the, 5'-Cp-N2-dG-3'-R-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' cross-link, the, (alpha)-CH3 group was positioned in the center of the minor groove, whereas for the 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3', cross-link, the (alpha)-CH3 group was positioned in the 3' direction, showing steric interference with the DNA helix. The, 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' cross-link exhibited a, lower thermal stability as evidenced by NMR spectroscopy as a function of, temperature. The two cross-links also exhibited apparent differences in, the conformation of the interstrand three-carbon cross-link, which may, also contribute to the lower apparent thermodynamic stability of the, 5'-Cp-N2-dG-3'-S-(alpha)-CH3-propyl-5'-Cp-N2-dG-3' cross-link.

About this Structure

2HMD is a Protein complex structure of sequences from [1]. Full crystallographic information is available from OCA.

Reference

Stereochemistry Modulates the Stability of Reduced Interstrand Cross-Links Arising from R- and S-alpha-CH(3)-gamma-OH-1,N(2)-Propano-2'-deoxyguanosine in the 5'-CpG-3' DNA Sequence., Cho YJ, Kozekov ID, Harris TM, Rizzo CJ, Stone MP, Biochemistry. 2007 Mar 13;46(10):2608-21. Epub 2007 Feb 17. PMID:17305317

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