Platinated DNA affects zinc finger conformation. Interaction of a platinated single-stranded oligonucleotide and the C-terminal zinc finger of nucleocapsid protein HIVNCp7.

This paper describes for the first time the intimate molecular details of the association between a platinated oligonucleotide and a zinc finger peptide. Site-specific platination of the guanine in a single-stranded hexanucleotide gave {[Pt(dien)d(5'-TACGCC-3')], Pt(dien)(6-mer)} (II) characterized by mass spectrometry and H-1 nuclear magnetic resonance (NMR) spectroscopy. The work extends the study of platinum-nucleobase complex-zinc finger interactions using small molecules such as [Pt(dien)(9-EtGua)](2+) (I). The structure of the (34-52) C-terminal finger of HIV nucleocapsid protein HIVNCp7 (ZF1) was characterized by H-1 NMR spectroscopy and compared with that of the N-terminal single finger and the two-finger "intact" NCp7. Interaction of II with ZF1 results in significant changes in comparison to the "free" uncomplexed hexanucleotide; the major changes occurring for Trp37 resonances that are broadened and moved upfield, and other major shifts are for Gln45 (H epsilon 21, H gamma 3, Q beta), Met46 (NH, H gamma 2), Lys47 (NH, Q gamma), and Glu50 (H gamma 2, H gamma 3). The Zn-Cys/His chemical shifts show only marginal deviations. The solution structures of ZF1 and the 6-mer-ZF1 and II-ZF1 adducts were calculated from the nuclear Overhauser effect spectroscopy-derived distance constraints. The DNA position in the II-ZF1 adduct is completely different than in the absence of platinum. Major differences are the appearance of new Met46-Cyt6 H5 and Trp37-Cyt5 HS contacts but severe weakening of the Trp37-Gua4 contact, attributed to the steric effects caused by Gua4 platination, accompanied by a change in the position of the aromatic ring. The results demonstrate the feasibility of targeting specific ZF motifs with DNA-tethered coordination compounds, such as Pt compounds and Co macrocycles, with implications for drug targetting and indeed the intimate mechanisms of DNA repair of platinated DNA.