Shape-selective recognition of a model okazaki fragment by geometrically-constrained bis-distamycins

William H. Gmeiner, Wei Cui, David E. Konerding, Paul A. Keifer, Sanjay K. Sharma, Ana Maria Soto, Luis A Marky, J. William Lown

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Okazaki fragments represent interesting targets for the design of anticancer drugs because of their selective occurrence during DNA replication, a process often elevated in aggressive malignancies. Structural studies have indicated a bend occurs in the helical axis at the junction region (JR) that joins the DNA duplex region (DDR) and the RNA-DNA hybrid duplex region (HDR) of model Okazaki fragments. To identify a structural motif that provides a shape complementary to the Okazaki fragment minor groove, we have investigated the binding of geometrically-constrained bis-distamycins to a model Okazaki fragment, [OKA], with a sequence derived from the genome of simian virus 40 (SV40). Both the JR and the DDR of [OKA] contain consecutive A/T base pairs that could accommodate distamycin binding. Of the six bis-distamycins selected for analysis, the two with a para configuration of the dis-tamycins on the benzene or pyridine scaffold bound [OKA] tightly (Kd ∼ 1O−8 M from ΔTM) while the four with a meta orientation did not bind. The two mono-distamycins studied also did not bind [OKA], Molecular modeling of the complex between the para bis-distamycin MT-9 and [OKA] revealed MT-9 adopted an S-shape complementary to the minor groove of the model Okazaki fragment.

Original languageEnglish (US)
Pages (from-to)507-518
Number of pages12
JournalJournal of Biomolecular Structure and Dynamics
Volume17
Issue number3
DOIs
StatePublished - Dec 1999

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Distamycins
DNA
Okazaki fragments
Simian virus 40
Drug Design
Benzene
DNA Replication
Base Pairing

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Gmeiner, W. H., Cui, W., Konerding, D. E., Keifer, P. A., Sharma, S. K., Soto, A. M., ... Lown, J. W. (1999). Shape-selective recognition of a model okazaki fragment by geometrically-constrained bis-distamycins. Journal of Biomolecular Structure and Dynamics, 17(3), 507-518. https://doi.org/10.1080/07391102.1999.10508381

Shape-selective recognition of a model okazaki fragment by geometrically-constrained bis-distamycins. / Gmeiner, William H.; Cui, Wei; Konerding, David E.; Keifer, Paul A.; Sharma, Sanjay K.; Soto, Ana Maria; Marky, Luis A; Lown, J. William.

In: Journal of Biomolecular Structure and Dynamics, Vol. 17, No. 3, 12.1999, p. 507-518.

Research output: Contribution to journalArticle

Gmeiner, William H. ; Cui, Wei ; Konerding, David E. ; Keifer, Paul A. ; Sharma, Sanjay K. ; Soto, Ana Maria ; Marky, Luis A ; Lown, J. William. / Shape-selective recognition of a model okazaki fragment by geometrically-constrained bis-distamycins. In: Journal of Biomolecular Structure and Dynamics. 1999 ; Vol. 17, No. 3. pp. 507-518.
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