NMR-based model of a telomerase-inhibiting compound bound to G- quadruplex DNA

Oleg Yu Fedoroff, Miguel Salazar, Haiyong Han, Violetta V. Chemeris, Sean M. Kerwin, Laurence Hurley

Research output: Contribution to journalArticle

333 Citations (Scopus)

Abstract

The single-stranded (TTAGGG)(n) tail of human telomeric DNA is known to form stable G-quadruplex structures. Optimal telomerase activity requires the nonfolded single-stranded form of the primer, and stabilization of the G- quadruplex form is known to interfere with telomerase binding. We have identified 3,4,9,10-perylenetetracarboxylic diimide-based ligands as potent inhibitors of human telomerase by using a primer extension assay that does not use PCR-based amplification of the telomerase primer extension products. A set of NMR titrations of the ligand into solutions of G-quadruplexes using various oligonucleotides related to human telomeric DNA showed strong and specific binding of the ligand to the G-quadruplex. The exchange rate between bound and free DNA forms is slow on the NMR time scale and allows the unequivocal determination of the binding site and mode of binding. In the case of the 5'-TTAGGG sequence, the ligand-DNA complex consists of two quadruplexes oriented in a tail-to-tail manner with the ligand sandwiched between terminal G4 planes. Longer telomeric sequences, such as TTAGGGTT, TTAGGGTTA, and TAGGGTTA, form 1:1 ligand-quadruplex complexes with the ligand bound at the GT step by a threading intercalation mode. On the basis of 2D NOESY data, a model of the latter complex has been derived that is consistent with the available experimental data. The determination of the solution structure of this telomerase inhibitor bound to telomeric quadruplex DNA should help in the design of new anticancer agents with a unique and novel mechanism of action.

Original languageEnglish (US)
Pages (from-to)12367-12374
Number of pages8
JournalBiochemistry
Volume37
Issue number36
DOIs
StatePublished - Sep 8 1998
Externally publishedYes

Fingerprint

G-Quadruplexes
Telomerase
Nuclear magnetic resonance
Ligands
DNA
Tail
Intercalation
Titration
Oligonucleotides
Antineoplastic Agents
Amplification
Assays
Stabilization
Binding Sites
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Biochemistry

Cite this

Fedoroff, O. Y., Salazar, M., Han, H., Chemeris, V. V., Kerwin, S. M., & Hurley, L. (1998). NMR-based model of a telomerase-inhibiting compound bound to G- quadruplex DNA. Biochemistry, 37(36), 12367-12374. https://doi.org/10.1021/bi981330n

NMR-based model of a telomerase-inhibiting compound bound to G- quadruplex DNA. / Fedoroff, Oleg Yu; Salazar, Miguel; Han, Haiyong; Chemeris, Violetta V.; Kerwin, Sean M.; Hurley, Laurence.

In: Biochemistry, Vol. 37, No. 36, 08.09.1998, p. 12367-12374.

Research output: Contribution to journalArticle

Fedoroff, OY, Salazar, M, Han, H, Chemeris, VV, Kerwin, SM & Hurley, L 1998, 'NMR-based model of a telomerase-inhibiting compound bound to G- quadruplex DNA', Biochemistry, vol. 37, no. 36, pp. 12367-12374. https://doi.org/10.1021/bi981330n
Fedoroff OY, Salazar M, Han H, Chemeris VV, Kerwin SM, Hurley L. NMR-based model of a telomerase-inhibiting compound bound to G- quadruplex DNA. Biochemistry. 1998 Sep 8;37(36):12367-12374. https://doi.org/10.1021/bi981330n
Fedoroff, Oleg Yu ; Salazar, Miguel ; Han, Haiyong ; Chemeris, Violetta V. ; Kerwin, Sean M. ; Hurley, Laurence. / NMR-based model of a telomerase-inhibiting compound bound to G- quadruplex DNA. In: Biochemistry. 1998 ; Vol. 37, No. 36. pp. 12367-12374.
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