NMR structure of dual site binding of mitoxantrone dimer to opposite grooves of parallel stranded G-quadruplex [d-(17GGGGT)]4

被引:14
作者
Pradeep, Tarikere Palakshan [1 ]
Barthwal, Ritu [1 ]
机构
[1] Indian Inst Technol Roorkee, Dept Biotechnol, Roorkee 247667, Uttar Pradesh, India
关键词
G-quadruplex; Mitoxantrone dimer; Nuclear magnetic resonance spectroscopy; Groove binding; Thermal stabilization; TELOMERIC G-QUADRUPLEX; SMALL-MOLECULE; ACTINOMYCIN-D; MINOR-GROOVE; DNA; RECOGNITION; INHIBITION; STABILIZATION; DERIVATIVES; SEQUENCE;
D O I
10.1016/j.biochi.2016.07.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The formation of complex between anti-cancer drug mitoxantrone (MTX) and tetra-molecular parallel G-quadruplex DNA [d-(TTGGGGT)](4) has been studied by solution state one and two dimensional NMR spectroscopy. Mitoxantrone forms a head-to-tail dimer and binds at two opposite grooves of the G-quadruplex. The Job's method of continuous variation and thermal melting studies independently ascertain binding stoichiometry of 4:1 in mitoxantrone:DNA complex. The existence of only four guanine NH peaks corresponding to the four G-quartets during the course of titration shows that C4 symmetry of G-quadruplex is intact upon binding of mitoxantrone. The specific inter molecular short distance contacts between protons of two mitoxantrone molecules of dimer, that is, ring A protons with ring C and side chain methylene protons, confirms the formation of mitoxantrone head-to-tail dimer. The observed 38 Nuclear Overhauser Enhancement (NOE) cross peaks between MTX and G-quadruplex DNA indicate formation of a well-defined complex. The three dimensional structure of 4:1 mitoxantrone:[d-(TTGGGGT)](4) complex computed by using experimental distance restraints followed by restrained Molecular Dynamics (rMD) simulations envisages the critical knowledge of specific molecular interactions within ligand-G-quadruplex complex. The findings are of direct interest in development of anti-cancer therapeutic drug based on G-quadruplex stabilization, resulting in telomerase inhibition. (C) 2016 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.
引用
收藏
页码:59 / 69
页数:11
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