Structural and thermodynamic studies of the interaction of distamycin A with the parallel quadruplex structure [d(TGGGGT)]4.
The complex between distamycin A and the parallel DNA quadruplex [d(TGGGGT)]4 has been studied by 1H NMR spectroscopy and isothermal titration calorimetry (ITC). To unambiguously assert that distamycin A interacts with the grooves of the quadruplex [d(TGGGGT)]4, we have analyzed the NMR titration profile of a modified quadruplex, namely [d(TGGMeGGT)]4, and we have applied the recently developed differential frequency-saturation transfer difference (DF-STD) method, for assessing the ligand-DNA binding mode. The three-dimensional structure of the 4:1 distamycin A/[d(TGGGGT)]4 complex has been determined by an in-depth NMR study followed by dynamics and mechanics calculations. All results unequivocally indicate that distamycin molecules interact with [d(TGGGGT)]4 in a 4:1 binding mode, with two antiparallel distamycin dimers that bind simultaneously two opposite grooves of the quadruplex. The affinity between distamycin A and [d(TGGGGT)]4 enhances ( approximately 10-fold) when the ratio of distamycin A to the quadruplex is increased. In this paper we report the first three-dimensional structure of a groove-binder molecule complexed to a DNA quadruplex structure.
Dipartimento di Chimica P. Corradini, Università degli Studi di Napoli Federico II, via Cintia, I-80126, Napoli, Italy.
Luigi
L
Martino
Ada
A
Virno
Bruno
B
Pagano
Antonella
A
Virgilio
Simone
S
Di Micco
Aldo
A
Galeone
Concetta
C
Giancola
Giuseppe
G
Bifulco
Luciano
L
Mayol
Antonio
A
Randazzo
D001483:Base Sequence; D002151:Calorimetry; D004247:DNA / Q000737:chemistry*; D004214:Distamycins / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013816:Thermodynamics
D004214:Distamycins; D008024:Ligands; C030000:stallimycin; D004247:DNA