DNA binding by analogues of the bifunctional intercalator TANDEM

Andrew J. Hampshire; David A. Rusling; Stephanie Bryan; David Paumier; Simon J. Dawson; John P. Malkinson; Mark Searcey; Keith R. Fox

doi:10.1021/bi800573p

DNA binding by analogues of the bifunctional intercalator TANDEM

Andrew J. Hampshire, David A. Rusling, Stephanie Bryan, David Paumier, Simon J. Dawson, John P. Malkinson, Mark Searcey, Keith R. Fox

School of Pharmacy & Biomedical Sciences

University Hospital Southampton NHS Foundation Trust

Research output: Contribution to journal › Article › peer-review

Abstract

We have used DNase I footprinting to study the binding strength and DNA sequence selectivity of novel derivatives of the quinoxaline bis-intercalator TANDEM. Replacing the valine residues in the cyclic octadepsipeptide with lysines does not affect the selectivity for TpA but leads to a 50-fold increase in affinity. In contrast, replacing both of the quinoxaline chromophores with naphthalene rings abolishes binding, while changing a single ring decreases the affinity, and footprints are observed at only the best binding sites (especially TATATA). By using fragments with different lengths of [(AT) n ], we demonstrate that these ligands bind best to the center of the longer (AT) n tracts.

Original language	English
Pages (from-to)	7900-7906
Number of pages	7
Journal	Biochemistry
Volume	47
Issue number	30
DOIs	https://doi.org/10.1021/bi800573p
Publication status	Published - 1 Jul 2008

Keywords

Binding Sites
DNA/chemistry
DNA Footprinting
Deoxyribonuclease I/metabolism
Intercalating Agents/chemistry
Lysine/chemistry
Models, Molecular
Naphthalenes/chemistry
Quinoxalines/chemistry
Valine/chemistry

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10.1021/bi800573p

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title = "DNA binding by analogues of the bifunctional intercalator TANDEM",

abstract = "We have used DNase I footprinting to study the binding strength and DNA sequence selectivity of novel derivatives of the quinoxaline bis-intercalator TANDEM. Replacing the valine residues in the cyclic octadepsipeptide with lysines does not affect the selectivity for TpA but leads to a 50-fold increase in affinity. In contrast, replacing both of the quinoxaline chromophores with naphthalene rings abolishes binding, while changing a single ring decreases the affinity, and footprints are observed at only the best binding sites (especially TATATA). By using fragments with different lengths of [(AT) n ], we demonstrate that these ligands bind best to the center of the longer (AT) n tracts.",

keywords = "Binding Sites, DNA/chemistry, DNA Footprinting, Deoxyribonuclease I/metabolism, Intercalating Agents/chemistry, Lysine/chemistry, Models, Molecular, Naphthalenes/chemistry, Quinoxalines/chemistry, Valine/chemistry",

author = "Hampshire, {Andrew J.} and Rusling, {David A.} and Stephanie Bryan and David Paumier and Dawson, {Simon J.} and Malkinson, {John P.} and Mark Searcey and Fox, {Keith R.}",

year = "2008",

month = jul,

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doi = "10.1021/bi800573p",

language = "English",

volume = "47",

pages = "7900--7906",

journal = "Biochemistry",

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publisher = "American Chemical Society",

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TY - JOUR

T1 - DNA binding by analogues of the bifunctional intercalator TANDEM

AU - Hampshire, Andrew J.

AU - Rusling, David A.

AU - Bryan, Stephanie

AU - Paumier, David

AU - Dawson, Simon J.

AU - Malkinson, John P.

AU - Searcey, Mark

AU - Fox, Keith R.

PY - 2008/7/1

Y1 - 2008/7/1

N2 - We have used DNase I footprinting to study the binding strength and DNA sequence selectivity of novel derivatives of the quinoxaline bis-intercalator TANDEM. Replacing the valine residues in the cyclic octadepsipeptide with lysines does not affect the selectivity for TpA but leads to a 50-fold increase in affinity. In contrast, replacing both of the quinoxaline chromophores with naphthalene rings abolishes binding, while changing a single ring decreases the affinity, and footprints are observed at only the best binding sites (especially TATATA). By using fragments with different lengths of [(AT) n ], we demonstrate that these ligands bind best to the center of the longer (AT) n tracts.

AB - We have used DNase I footprinting to study the binding strength and DNA sequence selectivity of novel derivatives of the quinoxaline bis-intercalator TANDEM. Replacing the valine residues in the cyclic octadepsipeptide with lysines does not affect the selectivity for TpA but leads to a 50-fold increase in affinity. In contrast, replacing both of the quinoxaline chromophores with naphthalene rings abolishes binding, while changing a single ring decreases the affinity, and footprints are observed at only the best binding sites (especially TATATA). By using fragments with different lengths of [(AT) n ], we demonstrate that these ligands bind best to the center of the longer (AT) n tracts.

KW - Binding Sites

KW - DNA/chemistry

KW - DNA Footprinting

KW - Deoxyribonuclease I/metabolism

KW - Intercalating Agents/chemistry

KW - Lysine/chemistry

KW - Models, Molecular

KW - Naphthalenes/chemistry

KW - Quinoxalines/chemistry

KW - Valine/chemistry

U2 - 10.1021/bi800573p

DO - 10.1021/bi800573p

M3 - Article

C2 - 18597492

SN - 0006-2960

VL - 47

SP - 7900

EP - 7906

JO - Biochemistry

JF - Biochemistry

IS - 30

ER -

DNA binding by analogues of the bifunctional intercalator TANDEM

Abstract

Keywords

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