2HMR

Solution structure of reduced interstrand cross-link arising from S-alpha-methyl-gamma-OH-1,N2-propano-2'-deoxyguanosine in the 5'-CpG-3' DNA sequence

Summary for 2HMR

• Entry DOI: 10.2210/pdb2hmr/pdb
• Related: 2HLI 2HMD
• Descriptor: DNA dodecamer with interstrand cross-link (2 entities in total)
• Functional Keywords: crotonaldehyde interstrand dna cross-link, dna
• Total number of polymer chains: 2
• Total formula weight: 7382.89

Authors

Cho, Y.-J.,Kozekov, I.D.,Harris, T.M.,Rizzo, C.J.,Stone, M.P. (deposition date: 2006-07-11, release date: 2007-03-13, Last modification date: 2024-05-29)

Primary citation

Cho, Y.-J.,Kozekov, I.D.,Harris, T.M.,Rizzo, C.J.,Stone, M.P.
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
Biochemistry, 46:2608-2621, 2007

PubMed Abstract: 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.

PubMed: 17305317
DOI: 10.1021/bi061381h

Experimental method

SOLUTION NMR