Structure of a nonanucleotide duplex cross-linked by cisplatin at an ApG sequence |
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Authors: | Marie-Hélène Fouchet Eric Guittet Jean A H Cognet Jiří Kozelka Corinne Gauthier Marc Le Bret Karel Zimmermann Jean-Claude Chottard |
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Institution: | (1) Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, URA CNRS 400, 45, rue des Saints-Pères, F-75270 Paris Cedex 06, France Tel.: +331-42 86 21 75; Fax +331-42 86 83 87; e-mail: kozelka@citi2.fr, FR;(2) Laboratoire de Résonance Magnétique Nucléaire, Institut de Chimie de Substances Naturelles, CNRS, F-91190 Gif-sur-Yvette, France, FR;(3) Laboratoire de Physicochimie Macromoléculaire, URA CNRS 147, U140 INSERM, Institut Gustave Roussy, F-94800 Villejuif, France, FR;(4) Unité de Bioinformatique, Batiment de Biotechnologie, INRA, F-78350 Jouy-en-Josas, France, FR |
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Abstract: | The structure of the second major adduct formed by the antitumor drug cisplatin with DNA, the intrastand cis–Pt(NH3)2{d(ApG)N7–N7} chelate (A*G*), has been investigated using a double-stranded nonanucleotide, d(CTCA*G*CCTC)-d(GAGGCTGAG), by means of NMR
and molecular modeling. The NMR data allow us to conclude that the oligonucleotide is kinked at the platinated site towards
the major groove in a way similar to that observed elsewhere for the G*G*-crosslink in d(GCCG*G*ATCGC)-d(GCGATCCGGC). The
main difference concerns the position of the thymine T(15) complementary to the platinated adenine A*(4). It remains stacked
on its 5′-neighbor C(14), corresponding to the "model E" described previously, whereas in the G*G*-adduct, the cytosine facing
the 5′-G* was found to oscillate between the 5′-branch ("model E") and the 3′-branch ("model C") of the complementary strand.
Two "E-type" models are presented which account for the particular NOE connectivity and for two remarkable upfield NMR signals:
those of the H2′ proton of the cytidine C(3) 5′ to the A*G* chelate, and of the H3 imino proton of T(15), the base complementary
to A*(4). The former shift is attributed to shielding by the destacked A*(4) base, whereas the latter is accounted for by
a swinging movement of the T(15) base between two positions where the imino Watson-Crick hydrogen bond with A*(4) remains
intact and the amino hydrogen bond is disrupted, or vice versa. Possible implications of the structural difference between
the AG and GG adducts of cisplatin in the mutagenic properties of the two adducts are discussed.
Received: 19 August 1996 / Accepted: 4 November 1996 |
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Keywords: | Cisplatin Antitumor drugs Nuclear magnetic resonance Molecular modeling |
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