Minor-Groove Binding Drugs: Where Is the Second Hoechst 33258 Molecule?

Handle URI:
http://hdl.handle.net/10754/598840
Title:
Minor-Groove Binding Drugs: Where Is the Second Hoechst 33258 Molecule?
Authors:
Fornander, Louise H.; Wu, Lisha; Billeter, Martin; Lincoln, Per; Nordén, Bengt
Abstract:
Hoechst 33258 binds with high affinity into the minor groove of AT-rich sequences of double-helical DNA. Despite extensive studies of this and analogous DNA binding molecules, there still remains uncertainty concerning the interactions when multiple ligand molecules are accommodated within close distance. Albeit not of direct concern for most biomedical applications, which are at low drug concentrations, interaction studies for higher drug binding are important as they can give fundamental insight into binding mechanisms and specificity, including drug self-stacking interactions that can provide base-sequence specificity. Using circular dichroism (CD), isothermal titration calorimetry (ITC), and proton nuclear magnetic resonance (1H NMR), we examine the binding of Hoechst 33258 to three oligonucleotide duplexes containing AT regions of different lengths: [d(CGCGAATTCGCG)]2 (A2T2), [d(CGCAAATTTGCG)]2 (A3T 3), and [d(CGAAAATTTTCG)]2 (A4T4). We find similar binding geometries in the minor groove for all oligonucleotides when the ligand-to-duplex ratio is less than 1:1. At higher ratios, a second ligand can be accommodated in the minor groove of A4T4 but not A2T2 or A3T3. We conclude that the binding of the second Hoechst to A4T4 is not cooperative and that the molecules are sitting with a small separation apart, one after the other, and not in a sandwich structure as previously proposed. © 2013 American Chemical Society.
Citation:
Fornander LH, Wu L, Billeter M, Lincoln P, Nordén B (2013) Minor-Groove Binding Drugs: Where Is the Second Hoechst 33258 Molecule? J Phys Chem B 117: 5820–5830. Available: http://dx.doi.org/10.1021/jp400418w.
Publisher:
American Chemical Society (ACS)
Journal:
The Journal of Physical Chemistry B
KAUST Grant Number:
KUK-11-008-23
Issue Date:
16-May-2013
DOI:
10.1021/jp400418w
PubMed ID:
23607615
Type:
Article
ISSN:
1520-6106; 1520-5207
Sponsors:
We acknowledge support from King Abdullah University of Science and Technology (KAUST, KUK-11-008-23) and the European Research Council (ERC-2008-AdG 227700). L.W. and M.B. thank the Swedish NMR center for instrumental time and support.
Appears in Collections:
Publications Acknowledging KAUST Support

Full metadata record

DC FieldValue Language
dc.contributor.authorFornander, Louise H.en
dc.contributor.authorWu, Lishaen
dc.contributor.authorBilleter, Martinen
dc.contributor.authorLincoln, Peren
dc.contributor.authorNordén, Bengten
dc.date.accessioned2016-02-25T13:42:13Zen
dc.date.available2016-02-25T13:42:13Zen
dc.date.issued2013-05-16en
dc.identifier.citationFornander LH, Wu L, Billeter M, Lincoln P, Nordén B (2013) Minor-Groove Binding Drugs: Where Is the Second Hoechst 33258 Molecule? J Phys Chem B 117: 5820–5830. Available: http://dx.doi.org/10.1021/jp400418w.en
dc.identifier.issn1520-6106en
dc.identifier.issn1520-5207en
dc.identifier.pmid23607615en
dc.identifier.doi10.1021/jp400418wen
dc.identifier.urihttp://hdl.handle.net/10754/598840en
dc.description.abstractHoechst 33258 binds with high affinity into the minor groove of AT-rich sequences of double-helical DNA. Despite extensive studies of this and analogous DNA binding molecules, there still remains uncertainty concerning the interactions when multiple ligand molecules are accommodated within close distance. Albeit not of direct concern for most biomedical applications, which are at low drug concentrations, interaction studies for higher drug binding are important as they can give fundamental insight into binding mechanisms and specificity, including drug self-stacking interactions that can provide base-sequence specificity. Using circular dichroism (CD), isothermal titration calorimetry (ITC), and proton nuclear magnetic resonance (1H NMR), we examine the binding of Hoechst 33258 to three oligonucleotide duplexes containing AT regions of different lengths: [d(CGCGAATTCGCG)]2 (A2T2), [d(CGCAAATTTGCG)]2 (A3T 3), and [d(CGAAAATTTTCG)]2 (A4T4). We find similar binding geometries in the minor groove for all oligonucleotides when the ligand-to-duplex ratio is less than 1:1. At higher ratios, a second ligand can be accommodated in the minor groove of A4T4 but not A2T2 or A3T3. We conclude that the binding of the second Hoechst to A4T4 is not cooperative and that the molecules are sitting with a small separation apart, one after the other, and not in a sandwich structure as previously proposed. © 2013 American Chemical Society.en
dc.description.sponsorshipWe acknowledge support from King Abdullah University of Science and Technology (KAUST, KUK-11-008-23) and the European Research Council (ERC-2008-AdG 227700). L.W. and M.B. thank the Swedish NMR center for instrumental time and support.en
dc.publisherAmerican Chemical Society (ACS)en
dc.titleMinor-Groove Binding Drugs: Where Is the Second Hoechst 33258 Molecule?en
dc.typeArticleen
dc.identifier.journalThe Journal of Physical Chemistry Ben
dc.contributor.institutionChalmers University of Technology, Göteborg, Swedenen
dc.contributor.institutionGoteborgs Universitet, Goteborg, Swedenen
kaust.grant.numberKUK-11-008-23en
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