Minor groove orientation of the KWKK peptide tethered via the N-terminal amine to the acrolein-derived 1,N2-gamma-hydroxypropanodeoxyguanosine lesion with a trimethylene linkage.
DNA-protein conjugates are potentially repaired via proteolytic digestion to DNA-peptide conjugates. The latter have been modeled with the amino-terminal lysine of the peptide KWKK conjugated via a trimethylene linkage to the N(2)-dG amine positioned in 5'-d(GCTAGCXAGTCC)-3'.5'-d(GGACTCGCTAGC)-3' (X = N(2)-dG-trimethylene link-KWKK). This linkage is a surrogate for the reversible linkage formed by the gamma-OH-1,N(2)-propanodeoxyguanosine (gamma-OH-PdG) adduct. This conjugated KWKK stabilizes the DNA. Amino acids K(26), W(27), K(28), and K(29) are in the minor groove. The W(27) indolyl group does not intercalate into the DNA. The G(7) N(2) amine and the K(26) N-terminal amine nitrogens are in the trans configuration with respect to the C(alpha) or C(gamma) of the trimethylene tether, respectively. The structure of this DNA-KWKK conjugate is discussed in the context of its biological processing.
Huang
Hai
H
Department of Chemistry, Center in Molecular Toxicology, Center for Structural Biology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, USA.
Kozekov
Ivan D
ID
Kozekova
Albena
A
Rizzo
Carmelo J
CJ
McCullough
Amanda K
AK
Lloyd
R Stephen
RS
Stone
Michael P
MP
D000171:Acrolein / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D003521:Cyclopropanes / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D004249:DNA Damage; D004260:DNA Repair; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry*
D000588:Amines; D003521:Cyclopropanes; D018736:DNA Adducts; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; C488128:alpha-hydroxypropanodeoxyguanosine; D000171:Acrolein; C030797:cyclopropane; D003849:Deoxyguanosine