Crystal structure of the [Mg2+-(chromomycin A3)2]-d(TTGGCCAA)2 complex reveals GGCC binding specificity of the drug dimer chelated by a metal ion.
The anticancer antibiotic chromomycin A3 (Chro) is a DNA minor groove binding drug belonging to the aureolic family. Chro likely exerts its activity by interfering with replication and transcription. Chro forms a dimer, mediated by a divalent metal ion, which binds to G/C-rich DNA. Herein we report the first crystal structure of Chro bound to d(TTG GCCAA)2 DNA duplex solved by multiwavelength anomalous diffraction (MAD) based on the chelated Co3+ ion. The structure of the Mg2+ complex was subsequently refined at 2.15 A resolution, which revealed two complexes of metal-coordinated dimers of Chro bound to the octamer DNA duplex in the asymmetric unit. The metal ion is octahedrally coordinated to the O1 and O9 oxygen atoms of the chromophore (CPH), and two water molecules act as the fifth and sixth ligands. The two coordinated water molecules are hydrogen bonded to O2 atoms of C5 and C13 bases. The Chro dimer binds at and significantly widens the minor groove of the GGCC sequence. The long axis of each chromophore lies along and stacks over the sugar-phosphate backbone with the two attached saccharide moieties (rings A/B and C/D/E) wrapping across the minor groove. DNA is kinked by 30 degrees and 36 degrees in the two complexes, respectively. Six G-specific hydrogen bonds between Chro and DNA provide the GGCC sequence specificity. Interestingly, DNA in concert with Chro appears to act as an effective template to catalyze the deamination of Co(NH3)6(3+), as shown by circular dichroism and crystal structure data. Our results present useful structural information for designing new anticancer drug derivatives in the future.
Hou
Ming-Hon
MH
Institute of Biological Chemistry, Academia Sinica, Taipei, 115 Taiwan.
Robinson
Howard
H
Gao
Yi-Gui
YG
Wang
Andrew H-J
AH
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002413:Cations, Divalent / Q000378:metabolism; D014128:Chromomycin A3 / Q000737:chemistry* / Q000378:metabolism*; D002942:Circular Dichroism; D003035:Cobalt / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D006860:Hydrogen Bonding; D008274:Magnesium / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D010100:Oxygen / Q000378:metabolism; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D002413:Cations, Divalent; D014867:Water; C030862:cobalt ammonium complex; D003035:Cobalt; D004247:DNA; D014128:Chromomycin A3; D008274:Magnesium; D010100:Oxygen