The crystal structure of the complex formed between the dodecanucleotide d(CGCGAATTCGCG)2 and the drug pentamidine, which is active against the Pneumocystis carinii pathogen in AIDS patients, has been determined to a resolution of 2.1 A and an R-factor of 19.4%. Analysis of the structure has shown the drug to be bound in the 5'-AATT minor groove region of the duplex, with the amidinium groups H-bonded to adenine N3 atoms in an interstrand manner. The drug molecule adopts an extended conformation, and the immediate binding site spans four base pairs. Structural details of the drug-DNA interactions are discussed, and comparison is made with the dodecamer complex of the structurally similar berenil ligand.

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The structure of the G-G mispaired dodecanucleotide d(CGCGAATTGGCG)2 has been solved by x-ray crystallography and refined to an R factor of 18.8% at 2.2 A resolution for 3513 reflections. The dodecamer crystallizes as a B-type DNA double helix. It contains two G(and){G(syn) base pairs-i.e., G-4/G-16(antd)G-21/G-9(syn). The Hoogsteen base pairing involves atoms 0-6 and N-7 of the guanne in the syn conformation with atoms N-1 and N-2 of the anti-paired purine. One G-G base pair has a bifurcated hydrogen bond between G-4(N-1).G-21(N-7) and G-4(N-1)-G-21(O-6). There is little overall structural distortion of the double helix induced as a consequence of the mispiring. The helical width is significantly increased by comparison with the structure of the native duplex, and the minor groove width in the 5'-AATT region is decreased. The GIG base pairing induces high-BIu phosphate conformations at residues G-9 and T-20 in addition to more normal Be conformations at G-10 and G-22. It is suggested that these backbone aberrations provide signals for the facile repairability of GIG mispairs in DNA.DNA base mispairings or mismatches occur as a consequence of errors in genetic recombination and/or replication (1-3). These errors are corrected by a repair system that recognizes the lesion, unwinds the duplex, and excises the newly synthesized strand. Purine-containing mispairs occur more frequently than pyrimidine-pyrimidine pairs, with the ARC and G-G mispairings being the most efficiently repaired. G-G base pairing plays a major role in stabilizing telomere structure (4-9) and is important in purine-purine DNA triplexes (10) and in various RNA stem bulges (11).Several models for G-G-mispaired structures have been proposed (see, for example, refs. 6, 8, 12, and 13). A G(anti)-G(syn) base arrangement has been suggested for the GIG pairing in a DNA duplex, while NMR data and molecular models suggest that the guanines are hydrogen-bonded in a cyclic fashion for the four-stranded quartet structure in telomeric DNA. NMR solution data for the d(GAGGAGGACG)-d(CGTGCGTCCTC) duplex, containing a central G-G mispair (14), suggest that the bases adopt a symmetrical anti-syn arrangement and are stacked into the helical axis. The hydrogen-bonding pattern preferred by these authors involves symmetric hydrogen bonding between the N-1 imino protons and the 0-6 carbonyl oxygen atom. A recent solution NMR analysis of the d(CGCGAATTGGCG)2 duplex indicates that the G(anti)-G(anti) conformation is favored at low temperatures and under high-salt conditions, with the structure characterized by non-hydrogen-bonded G&G base pairs. This conformation is, however, unstable at higher temperatures, as judged by spectral heterogeneity, with the mispairing bases providing a focus for localized melting. Localized DNA bulges were considered to result from unusual phosphate backbone torsion angles in the vicinity of the G-G sites (15). In contrast, the recently reported crystal structure and NMR analysis of the four-stranded d(G4T4G4)2 sequence from the 3'...