Nucleic Acids Research Advance Access originally published online on March 2, 2009
Nucleic Acids Research 2009 37(8):2434-2448; doi:10.1093/nar/gkp029
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nucleic Acids Research, 2009, Vol. 37, No. 8 2434-2448
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Computational Biology |
Structural basis for the sequence-dependent effects of platinum–DNA adducts
1Department of Biochemistry and Biophysics, 2Molecular and Cellular Biophysics Program and 3Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599-7260, USA
*To whom correspondence should be addressed. Tel: +1 919 966 3286; Fax: +1 919 966 2852; Email: stephen_chaney{at}med.unc.edu Correspondence may also be addressed to Dr Nikolay V. Dokholyan. Tel: +1 919 843 2513; Email: dokh{at}med.unc.edu
Received October 13, 2008. Revised December 23, 2008. Accepted January 8, 2009.
The differences in efficacy and molecular mechanisms of platinum based anti-cancer drugs cisplatin (CP) and oxaliplatin (OX) have been hypothesized to be in part due to the differential binding affinity of cellular and damage recognition proteins to CP and OX adducts formed on adjacent guanines in genomic DNA. HMGB1a in particular exhibits higher binding affinity to CP-GG adducts, and the extent of discrimination between CP- and OX-GG adducts is dependent on the bases flanking the adducts. However, the structural basis for this differential binding is not known. Here, we show that the conformational dynamics of CP- and OX-GG adducts are distinct and depend on the sequence context of the adduct. Molecular dynamics simulations of the Pt-GG adducts in the TGGA sequence context revealed that even though the major conformations of CP- and OX-GG adducts were similar, the minor conformations were distinct. Using the pattern of hydrogen bond formation between the Pt–ammines and the adjacent DNA bases, we identified the major and minor conformations sampled by Pt–DNA. We found that the minor conformations sampled exclusively by the CP-GG adduct exhibit structural properties that favor binding by HMGB1a, which may explain its higher binding affinity to CP-GG adducts, while these conformations are not sampled by OX-GG adducts because of the constraints imposed by its cyclohexane ring, which may explain the negligible binding affinity of HMGB1a for OX-GG adducts in the TGGA sequence context. Based on these results, we postulate that the constraints imposed by the cyclohexane ring of OX affect the DNA conformations explored by OX-GG adduct compared to those of CP-GG adduct, which may influence the binding affinities of HMG-domain proteins for Pt-GG adducts, and that these conformations are further influenced by the DNA sequence context of the Pt-GG adduct.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Zhu, Y. Wang, and G. Chen Differences in conformational dynamics of [Pt3(HPTAB)]6+-DNA adducts with various cross-linking modes Nucleic Acids Res., September 1, 2009; 37(17): 5930 - 5942. [Abstract] [Full Text] [PDF]
|
|