A high-resolution structure of a DNA-chromomycin-Co(II) complex determinedfrom pseudocontact shifts in nuclear magnetic resonance

Background: The drug chromomycin-A(3) binds to the minor groove of DNA and requires a divalent metal ion for complex formation. H-1, P-31 and C-13 pse udocontact shifts occurring in the presence of a tightly bound divalent cob alt ion in the complex between d(TTGGCCAA)(2) and chromomycin-A(3) have bee n used to determine the structure of the complex. The accuracy of the struc ture was verified by validation with nuclear Overhauser enhancements (NOEs) and J-coupling constants not used in the structure calculation. Results: The final structure was determined to 0.7 Angstrom resolution, The structure was compared with a structure obtained in an earlier study using NOEs, in order to assess the accuracy of NOEs in giving global structural information for a DNA complex. Although some basic features of the structur es agreed, they differed substantially in the fine structural details and i n the DNA axis curvature generated by the drug. The distortion of base-pair planarity that was observed in the NOE structure was not seen in our struc ture. Differences in drug orientation and hydrogen bonding also occurred. T he curvature and elongation of the DNA that was obtained previously was not found to occur in our study. Conclusions: The use of pseudocontact shifts has enabled us to obtain a hig h-precision global structure of the chromomycin-DNA complex, which provides an accurate template on which to consider targeting minor groove binding d rugs. The effect of such binding is not propagated far along the helix but is restricted to a local kink in the axis that reverts to its original dire ction within four base pairs.