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| Home > Publications database > Structure of human telomere G-quadruplex in the presence of a model drug along the thermal unfolding pathway |
| Home > Publications database > Structure of human telomere G-quadruplex in the presence of a model drug along the thermal unfolding pathway |
| Journal Article | FZJ-2019-00049 |
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2018
Oxford Univ. Press
Oxford
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Please use a persistent id in citations: http://hdl.handle.net/2128/21138 doi:10.1093/nar/gky1092
Abstract: A multi-technique approach, combining circular dichroism spectroscopy, ultraviolet resonance Raman spectroscopy and small angle scattering techniques, has been deployed to elucidate how the structural features of the human telomeric G-quadruplex d[A(GGGTTA)3GGG] (Tel22) change upon thermal unfolding. The system is studied both in the free form and when it is bound to Actinomycin D (ActD), an anticancer ligand with remarkable conformational flexibility. We find that at room temperature binding of Tel22 with ActD involves end-stacking upon the terminal G-tetrad. Structural evidence for drug-driven dimerization of a significant fraction of the G-quadruplexes is provided. When the temperature is raised, both free and bound Tel22 undergo melting through a multi-state process. We show that in the intermediate states of Tel22 the conformational equilibrium is shifted toward the (3+1) hybrid-type, while a parallel structure is promoted in the complex. The unfolded state of the free Tel22 is consistent with a self-avoiding random-coil conformation, whereas the high-temperature state of the complex is observed to assume a quite compact form. Such an unprecedented high-temperature arrangement is caused by the persistent interaction between Tel22 and ActD, which stabilizes compact conformations even in the presence of large thermal structural fluctuations.
Keyword(s): Health and Life (1st) ; Soft Condensed Matter (2nd) ; Biology (2nd)
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