Journal Article

FZJ-2019-00049

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structure of human telomere G-quadruplex in the presence of a model drug along the thermal unfolding pathway

Bianchi, F. ; Comez, L. (Corresponding author) ; Biehl, R.FZJ* ; D’Amico, F. ; Gessini, A. ; Longo, M.FZJ* ; Masciovecchio, C. ; Petrillo, C. ; Radulescu, A.FZJ* ; Rossi, B. ; Sacchetti, F. ; Sebastiani, F. ; Violini, N.FZJ* ; Paciaroni, A.

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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Contributing Institute(s):

1. JCNS-FRM-II (JCNS-FRM-II)
2. Neutronenstreuung (Neutronenstreuung ; JCNS-1)

Research Program(s):

1. 6215 - Soft Matter, Health and Life Sciences (POF3-621) (POF3-621)
2. 6G15 - FRM II / MLZ (POF3-6G15) (POF3-6G15)
3. 6G4 - Jülich Centre for Neutron Research (JCNS) (POF3-623) (POF3-623)

Experiment(s):

1. KWS-2: Small angle scattering diffractometer (NL3ao)

Appears in the scientific report 2018

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