An NMR study of [d(CGCGAATTCGCG)]2 containing an interstrand cross-link derived from a distamycin-pyrrole conjugate.
Minor groove binding compounds related to distamycin A bind DNA with high sequence selectivity, recognizing sites which contain various combinations of A.T and G.C base pairs. These molecules have the potential to deliver cross-linking agents to the minor groove of a target DNA sequence. We have studied the covalent DNA-DNA cross-linked complex of 2,3- bis(hydroxymethyl)pyrrole-distamycin and [d(CGCGAATTCGCG)]2. The alkylating pyrrole design is based on the pharmacophore of mitomycin C and is similar in substructure to another important class of natural products, the oxidatively activated pyrrolizidine alkaloids. Ligand-DNA NOEs confirm that the tri(pyrrole-carboxamide) unit of the ligand is bound in the minor groove of the central A+T tract. Unexpectedly, it is shifted by 1 bp with respect to the distamycin A binding site on this DNA sequence. The cross-link bridges the 2-amino position of two guanine residues, G4 and G22. The C3.G22 and G4.C21 base pairs exhibit Watson-Crick base pairing, with some local distortion, as evidenced by unusual intensities observed for DNA-DNA NOE cross-peaks. The model is compared with a related structure of a cross-linked mitomycin C:DNA complex.
Fagan
P A
PA
Structural Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Spielmann
H P
HP
Sigurdsson
S
S
Rink
S M
SM
Hopkins
P B
PB
Wemmer
D E
DE
D001483:Base Sequence; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry*; D004214:Distamycins / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*
D003432:Cross-Linking Reagents; D004214:Distamycins; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D011758:Pyrroles; C030000:stallimycin; D004247:DNA