Defining GC-specificity in the minor groove: side-by-side binding of the di-imidazole lexitropsin to C-A-T-G-G-C-C-A-T-G

Abstract

Im and Py rings distinguish AT from GC base pairs because of steric factors involving the bulk of the guanine amine, and the ability of Im to form a hydrogen bond with the amine. Side-by-side Im and Py rings differentiate GC from CG base pairs because of tight steric contacts and sp2 hybridization at the amine nitrogen atom, with the favored conformations being G/Im,Py/C and C/Py,Im/G. Discrimination between AT and TA base pairs may be possible using bulkier rings, such as thiazole to select the A end of the base pair.

Structure of a β-Alanine-linked Polyamide Bound to a Full Helical Turn of Purine Tract DNA in the 1:1 Motif

“…1,15 Attempts have been made to verify this specific interaction in X-ray cocrystal structure analysis of imidazole-containing netropsin analogs with DNA sequences containing G/C base-pairs. 45,46 However, Im does not bind across from G in these structures, and therefore the key Im-N3 to G-NH2 hydrogen bond in 1:1 binding has yet to be verified by a high-resolution structure. Considerable X-ray and NMR structural data exist to support the formation of Im-N3 to G-NH2 hydrogen bonds for the Im/Py pair in the 2:1 motif.…”

Dimerization Energetics of DNA Minor Groove Binders

“…At the same time, it is known that similar interactions play an important role in the stabilization of protein structures (see review [32]). Two types of overlapping between aromatic rings and peptide bonds are possible in dimers: stagger and maximum [31]. In the case of the examined lexitropsins, the former is realized in three-ring molecules (AR, DM, and TZA) with a peptide group at the N-end, and the latter in four-ring ones (PA1 to PA4) without this group (see Fig.…”

“…The specific interaction between them and the physical reasons for such an arrangement remain almost obscured. Some authors mentioned the importance of their mutual polarization [31]. At the same time, it is known that similar interactions play an important role in the stabilization of protein structures (see review [32]).…”

Structure of the side-by-side binding of distamycin to d(GTATATAC)2

“…In contrast, the pyrrole± pyrrole pair binds A±T and T±A indiscriminately, while the imidazole±imidazole pair appears to favor G±C/C±G pairs (White et al, 1997;Kopka et al, 1997). Indeed, the synthetic drug di-imidazole lexitropsin (Kopka et al, 1997) and a pyrrole±imidazole polypeptide (Fig. 1) (Kielkopf et al, 1998) differentiate G±C from C±G and also from A±T and T±A in this binding mode.…”

“…The side-by-side drug binding led to new design principles for recognition of G±C/C±G base pairs with sequence speci®city (Mrksich & Dervan, 1993;Geierstanger et al, 1994;Geierstanger & Wemmer, 1995) and provided sequence-reading rules for the imidazole±pyrrole pair, which can differentiate G±C from C±G (White et al, 1997). In contrast, the pyrrole± pyrrole pair binds A±T and T±A indiscriminately, while the imidazole±imidazole pair appears to favor G±C/C±G pairs (White et al, 1997;Kopka et al, 1997). Indeed, the synthetic drug di-imidazole lexitropsin (Kopka et al, 1997) and a pyrrole±imidazole polypeptide (Fig.…”