Comparison of DNA complex formation behaviour for two closely related lexitropsin analogues

J.A. Parkinson, A.I. Khalaf, N.G. Anthony, S.P. Mackay, C.J. Suckling, R.D. Waigh

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Two closely related lexitropsin analogues that differ only in the form of the headgroup functionality (CHO (for 1) vs. Ac (for 2)) have been studied in their DNA-binding capacity for the sequence d(GCATATATGC) using 1H-NMR spectroscopy. DNA-Complex formation for the CHO derivative was apparent from the observation of new NMR signals on titration of DNA with ligand. Detailed investigation and assignment of the data for a ligand/DNA-duplex ratio of 2 : 1 clearly delineated the structure as one associated with the minor groove class of DNA complexes. The structure of the complex was determined on the basis of the acquired NMR data. Features characteristic of typical 2 : 1 minor-groove complexes were apparent. In a similar experimental approach, the Ac analogue ligand-DNA binding response was investigated. Despite the close similarity in chemical structure to the CHO case, the Ac analogue was found to produce NMR data of a much poorer quality. This was attributed to more rapid on/off chemical exchange equilibrium between ligand and DNA. From close analysis and comparison of the NMR data for the Ac and CHO headgroup ligand-DNA complexes, it was possible to ascertain that the same type of complex formed in each case but with different relative binding constants. Consideration of the nature and form of these complexes has been made with reference to a previously determined structure from our laboratory for the related lexitropsin analogue thiazotropsin A.
LanguageEnglish
Pages795-822
Number of pages27
JournalHelvetica Chimica Acta
Volume92
Issue number5
DOIs
Publication statusPublished - 2009

Fingerprint

DNA
deoxyribonucleic acid
analogs
Ligands
nuclear magnetic resonance
ligands
Nuclear magnetic resonance
grooves
lexitropsin
Titration
titration
Nuclear magnetic resonance spectroscopy
Magnetic Resonance Spectroscopy
Observation
Derivatives
spectroscopy

Keywords

  • Lexitropsin
  • DNA
  • minor groove binder
  • NMR spectroscopy
  • molecular dynamics calculation
  • peptide DNA complexes

Cite this

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title = "Comparison of DNA complex formation behaviour for two closely related lexitropsin analogues",
abstract = "Two closely related lexitropsin analogues that differ only in the form of the headgroup functionality (CHO (for 1) vs. Ac (for 2)) have been studied in their DNA-binding capacity for the sequence d(GCATATATGC) using 1H-NMR spectroscopy. DNA-Complex formation for the CHO derivative was apparent from the observation of new NMR signals on titration of DNA with ligand. Detailed investigation and assignment of the data for a ligand/DNA-duplex ratio of 2 : 1 clearly delineated the structure as one associated with the minor groove class of DNA complexes. The structure of the complex was determined on the basis of the acquired NMR data. Features characteristic of typical 2 : 1 minor-groove complexes were apparent. In a similar experimental approach, the Ac analogue ligand-DNA binding response was investigated. Despite the close similarity in chemical structure to the CHO case, the Ac analogue was found to produce NMR data of a much poorer quality. This was attributed to more rapid on/off chemical exchange equilibrium between ligand and DNA. From close analysis and comparison of the NMR data for the Ac and CHO headgroup ligand-DNA complexes, it was possible to ascertain that the same type of complex formed in each case but with different relative binding constants. Consideration of the nature and form of these complexes has been made with reference to a previously determined structure from our laboratory for the related lexitropsin analogue thiazotropsin A.",
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Comparison of DNA complex formation behaviour for two closely related lexitropsin analogues. / Parkinson, J.A.; Khalaf, A.I.; Anthony, N.G.; Mackay, S.P.; Suckling, C.J.; Waigh, R.D.

In: Helvetica Chimica Acta, Vol. 92, No. 5, 2009, p. 795-822.

Research output: Contribution to journalArticle

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AU - Parkinson, J.A.

AU - Khalaf, A.I.

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AU - Suckling, C.J.

AU - Waigh, R.D.

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AB - Two closely related lexitropsin analogues that differ only in the form of the headgroup functionality (CHO (for 1) vs. Ac (for 2)) have been studied in their DNA-binding capacity for the sequence d(GCATATATGC) using 1H-NMR spectroscopy. DNA-Complex formation for the CHO derivative was apparent from the observation of new NMR signals on titration of DNA with ligand. Detailed investigation and assignment of the data for a ligand/DNA-duplex ratio of 2 : 1 clearly delineated the structure as one associated with the minor groove class of DNA complexes. The structure of the complex was determined on the basis of the acquired NMR data. Features characteristic of typical 2 : 1 minor-groove complexes were apparent. In a similar experimental approach, the Ac analogue ligand-DNA binding response was investigated. Despite the close similarity in chemical structure to the CHO case, the Ac analogue was found to produce NMR data of a much poorer quality. This was attributed to more rapid on/off chemical exchange equilibrium between ligand and DNA. From close analysis and comparison of the NMR data for the Ac and CHO headgroup ligand-DNA complexes, it was possible to ascertain that the same type of complex formed in each case but with different relative binding constants. Consideration of the nature and form of these complexes has been made with reference to a previously determined structure from our laboratory for the related lexitropsin analogue thiazotropsin A.

KW - Lexitropsin

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KW - molecular dynamics calculation

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