2KNL

Structure of the trimethylene N2-dG:N2-dG interstrand cross-link in the 5'-GpC-3' sequence context

Summary for 2KNL

• Entry DOI: 10.2210/pdb2knl/pdb
• Related: 1LUH 2KNK
• Descriptor: DNA (5'-D(*TP*CP*CP*GP*CP*GP*GP*A)-3'), PROPANE (2 entities in total)
• Functional Keywords: interstrand cross-link, trimethylene, gpc sequence context, dna
• Total number of polymer chains: 2
• Total formula weight: 4899.31

Authors

Huang, H.,Dooley, P.A.,Harris, C.M.,Harris, T.M.,Stone, M.P. (deposition date: 2009-08-26, release date: 2009-09-29, Last modification date: 2024-05-22)

Primary citation

Huang, H.,Dooley, P.A.,Harris, C.M.,Harris, T.M.,Stone, M.P.
Differential base stacking interactions induced by trimethylene interstrand DNA cross-links in the 5'-CpG-3' and 5'-GpC-3' sequence contexts.
Chem.Res.Toxicol., 22:1810-1816, 2009

PubMed Abstract: Synthetically derived trimethylene interstrand DNA cross-links have been used as surrogates for the native cross-links that arise from the 1,N(2)-deoxyguanosine adducts derived from alpha,beta-unsaturated aldehydes. The native enal-mediated cross-linking occurs in the 5'-CpG-3' sequence context but not in the 5'-GpC-3' sequence context. The ability of the native enal-derived 1,N(2)-dG adducts to induce interstrand DNA cross-links in the 5'-CpG-3' sequence as opposed to the 5'-GpC-3' sequence is attributed to the destabilization of the DNA duplex in the latter sequence context. Here, we report higher accuracy solution structures of the synthetically derived trimethylene cross-links, which are refined from NMR data with the AMBER force field. When the synthetic trimethylene cross-links are placed into either the 5'-CpG-3' or the 5'-GpC-3' sequence contexts, the DNA duplex maintains B-DNA geometry with structural perturbations confined to the cross-linked base pairs. Watson-Crick hydrogen bonding is conserved throughout the duplexes. Although different from canonical B-DNA stacking, the cross-linked and the neighbor base pairs stack in the 5'-CpG-3' sequence. In contrast, the stacking at the cross-linked base pairs in the 5'-GpC-3' sequence is greatly perturbed. The pi-stacking interactions between the cross-linked and the neighbor base pairs are reduced. This is consistent with remarkable chemical shift perturbations of the C(5) H5 and H6 nucleobase protons that shifted downfield by 0.4-0.5 ppm. In contrast, these chemical shift perturbations in the 5'-CpG-3' sequence are not remarkable, consistent with the stacked structure. The differential stacking of the base pairs at the cross-linking region probably explains the difference in stabilities of the trimethylene cross-links in the 5'-CpG-3' and 5'-GpC-3' sequence contexts and might, in turn, account for the sequence selectivity of the interstrand cross-link formation induced by the native enal-derived 1,N(2)-dG adducts.

PubMed: 19916525
DOI: 10.1021/tx900225c

Experimental method

SOLUTION NMR