DNA adducts of the enantiomers of the Pt(II) complexes of the ahaz ligand (ahaz=3-aminohexahydroazepine) and recognition of these adducts by HMG domain proteins.
The bending, unwinding, and structural changes in DNA caused by the binding of each of the enantiomers of the platinum(II) complexes of the ahaz ligand (R- and S-[PtCl(2)(ahaz)], ahaz=3-aminohexahydroazepine) have been studied using 20-23 bp oligonucleotides containing TGGT and CGGA-binding sites as has the recognition of the adducts by HMG domain proteins. The domain A of HMGB1 (HMGB1a protein) binds to the adduct formed by the R enantiomer at the CGGA sequence with a similar high affinity as it does to the adduct of antitumor cisplatin, and to the adduct formed by the S enantiomer with a slightly lower affinity. In contrast, HMGB1a binds much more weakly to the ahaz adducts than to the cisplatin adducts formed at the TGGT sequence, with the binding to the adduct formed by the R enantiomer being weakest. Each enantiomer and cisplatin cause unwinding of both sequences that is in the narrow range, 19-22 degrees. There are modest but significant differences in the degree of bending induced, with the S enantiomer causing the least bending, cisplatin intermediate, and the R enantiomer the most. Molecular modeling of the {Pt(ahaz)}/GG adducts in 8-bp models reveals significant differences in the local distortion at the GG-binding sites depending on the flanking bases and shows that interactions between the thymine methyl groups and the ahaz ligand are likely to inhibit bending of the TGGT sequence.
Malina
Jaroslav
J
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Vojtiskova
Marie
M
Brabec
Viktor
V
Diakos
Connie I
CI
Hambley
Trevor W
TW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D002945:Cisplatin / Q000494:pharmacology; D018736:DNA Adducts; D024243:HMGB1 Protein / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013941:Thymine / Q000737:chemistry
C105315:(3-aminohexahydroazepine)dichloroplatinum(II); D000970:Antineoplastic Agents; D018736:DNA Adducts; D024243:HMGB1 Protein; D008024:Ligands; D009841:Oligonucleotides; D009942:Organometallic Compounds; D002945:Cisplatin; D013941:Thymine