A DNA–porphyrin minor-groove complex at atomic resolution: The structural consequences of porphyrin ruffling

Abstract

The crystal structure of a B-type DNA hexanucleotide duplex complexed with the porphyrin molecule nickel-[tetra-N-methylpyridyl] porphyrin has been solved by multiwavelength anomalous diffraction phasing and refined to an R factor of 11.5% at a resolution of 0.9 Å. The structure has been solved and refined as two crystallographically independent duplexes, stacked end to end. Contrary to expectation, the porphyrin molecule is not intercalated into the duplex but is stacked onto the ends of the two-duplex stack. The porphyrin molecule is highly buckled as a consequence of the nickel coordination, which produces large changes in local DNA structure. A second mode of porphyrin binding is apparent as a consequence of crystal packing, which places the ligand in the minor groove of an adjacent duplex. This structure thus provides, to our knowledge, the first atomic visualization of minor-groove binding for a porphyrin molecule. The geometry of groove binding provides a ready explanation for porphyrin-induced DNA strand cleavage at deoxyribose residues.DNA structure ͉ minor groove binding ͉ end capping T he interactions of cationic porphyrins with nucleic acids have received considerable attention (1, 2). Several have clinical potential as anticancer agents in photodynamic therapy (3, 4), probably as a consequence of their ability to selectively accumulate on the surface of tumor cells, become internalized, bind to genomic DNA, and then induce DNA strand cleavage. One such compound is tetra-(N-methylpyridyl) porphyrin (TMPy: Fig. 1a), which can be coordinated with a range of transition metals (1, 2, 5, 6). TMPy has more direct antitumor activity, possibly as a consequence of its ability to inhibit the telomerase enzyme (7). Binding to quadruplex DNA as well as to duplexes has been reported for TMPy and various complexes (8-10). Stabilization of G-quadruplex structures has been shown to be the mechanism whereby TMPy inhibits telomerase from catalyzing the synthesis of further linear telomere repeats. NMR and photocleavage data have been interpreted in favor of a model with a TMPy molecule externally stacking onto guaninequadruplex structures (8-10).Noncovalent interactions of TMPy and its metal complexes with duplex DNA are sequence dependent (2, 11), with intercalation occurring at 5Ј-CpG sites, as shown by NMR and other biophysical studies (12, 13) as well as molecular modeling (13,14). A crystallographic analysis (15) of the Cu 2ϩ complex of TMPy bound to the sequence 5Ј-d(CGTACG) 2 also found the ligand intercalated at this site, but with the 5Ј-end cytosine swung out in an extrahelical arrangement. By contrast, biophysical and modeling (14, 16) studies have suggested that TMPy itself (and many of its metal complexes) bind in the minor groove at A͞T sequences and perturb the double helix only to a minimal extent at such sites (16). No structural data has been reported to date on groove-binding modes. TMPy itself is a planar molecule (14, 15), and it has been assumed that the groove binding would therefore be analogou...

Small-molecule interaction with a five-guanine-tract G-quadruplex structure from the human MYC promoter

“…The position of TMPyP4 within the complex was incrementally changed twice by a 15° rotation around the axis of the Pu24I G-tetrad core. In each of the three positions of TMPyP4 within the complex, angles between pyridyl rings and the porphyrin were initially set to ±60°, corresponding to previously reported crystal structure of the ligand 45 and favorable van der Waals energy term. Next, the force constant for the torsion angle between pyridyl rings and the porphyrin was set to 0 (that is, free rotation was allowed); molecular dynamics and energy minimization was performed again for six complexes.…”

Zn Ions Change Binding Mode of TOEPyP4 with DNA and Cause DNA Transition from B to C and Zn-Like Conformations

“…These porphyrins bind to DNA and polynucleotides, and form two main binding modes-intercalation into GCrich regions and external groove binding in AT-rich regions [8,13,16]. Both binding modes are able to transfer DNA and polynucleotides from B to Z-like conformation [8,9].…”

CD and DSC Investigation of Individual and Complex Influence of Meso-Tetra(4-Oxiethylpyridil) Porphyrin (TOEPyP4) and Its Zn-Complex on DNA

“…It predominantly accumulates in tumor cells and binds to G-quadruplex of telomeric DNA [1,2], and defends it from high telomerase activity detaining growth of transformed cells in case of many leukemic diseases [3,4]. Its metal complexes can induce DNA strand cleavage at deoxyribose residues and initiate apoptosis of cancer cells [5]. In the classic works [6][7][8][9], the absorption mechanisms of the TMPyP4 porphyrins into DNA, AT and GT oligomers, and polynucleotide were investigated with the help of different physical technologies.…”