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.
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'...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.