Spectroscopic elucidation of the inhibitory mechanism of Cys 2His2 zinc finger transcription factors by cobalt(III) schiff base complexes

Marie Heffern, Josh W. Kurutz, Thomas J. Meade

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Transcription factors are key regulators in both normal and pathological cell processes. Affecting the activity of these proteins is a promising strategy for understanding gene regulation and developing effective therapeutics. CoIII Schiff base complexes ([Co(acacen)(L)2]+ where L=labile axial ligands) have been shown to be potent inhibitors of a number of zinc metalloproteins including Cys2His2 zinc finger transcription factors. Inhibition by [Co(acacen)(L)2] + of the target protein is believed to occur through a dissociative exchange of the labile axial ligands for histidine (His) residues essential for function. Here, we report a series of spectroscopic investigations with model peptides of zinc fingers that elucidate the interaction between [Co(acacen)(L)2]+ complexes and zinc finger transcription factors. Observed changes in NMR chemical shifts and 2D 1H- 1H NOESY NMR spectra demonstrate the preference of [Co(acacen)(L)2]+ complexes to coordinate His residues over other amino acids. The conformation of [Co(acacen)(L)2] + upon His coordination was characterized by 1H NMR spectroscopy, near-UV CD, and electronic absorption. These studies reveal that the resulting His-coordinated [Co(acacen)(L)2]+ complex possesses an octahedral structure. The effects of [Co(acacen)(L) 2]+ complexes on the zinc-finger structure were assessed by the degree of hydrogen bonding (probed by 2D NMR spectroscopy) and secondary-structure profiles measured by far-UV CD. These structural studies demonstrate the ability of [Co(acacen)(L)2]+ complexes to disrupt the ββα structure of zinc fingers, resulting in primarily random-coil conformations. A mechanism is described wherein [Co(acacen)(L)2]+ complexes inhibit zinc finger transcription factor activity through selectively coordinating His residues in the zinc finger by dissociative ligand exchange and disrupting the ββα structural motif required for gene regulation. Uncrossing fingers: Transition-metal complexes are emerging as promising zinc finger transcription factor inhibitors (see scheme). The dynamic structure of zinc fingers can make inhibition difficult to characterize. An array of spectroscopic studies is described to elucidate the specific interaction between cobalt(III) complexes and zinc-finger peptides.

Original languageEnglish (US)
Pages (from-to)17043-17053
Number of pages11
JournalChemistry - A European Journal
Volume19
Issue number50
DOIs
StatePublished - Dec 9 2013
Externally publishedYes

Fingerprint

Transcription factors
Schiff Bases
Cobalt
Zinc
Transcription Factors
Histidine
Ligands
Gene expression
Peptides
Nuclear magnetic resonance spectroscopy
Conformations
Nuclear magnetic resonance
Metalloproteins
Proteins
Coordination Complexes
Chemical shift
Metal complexes
Transition metals
Amino acids
Hydrogen bonds

Keywords

  • cobalt
  • Schiff bases
  • spectroscopy
  • transcription factors
  • zinc fingers

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Spectroscopic elucidation of the inhibitory mechanism of Cys 2His2 zinc finger transcription factors by cobalt(III) schiff base complexes. / Heffern, Marie; Kurutz, Josh W.; Meade, Thomas J.

In: Chemistry - A European Journal, Vol. 19, No. 50, 09.12.2013, p. 17043-17053.

Research output: Contribution to journalArticle

@article{805dff46a72048168e3dec4f83520a68,
title = "Spectroscopic elucidation of the inhibitory mechanism of Cys 2His2 zinc finger transcription factors by cobalt(III) schiff base complexes",
abstract = "Transcription factors are key regulators in both normal and pathological cell processes. Affecting the activity of these proteins is a promising strategy for understanding gene regulation and developing effective therapeutics. CoIII Schiff base complexes ([Co(acacen)(L)2]+ where L=labile axial ligands) have been shown to be potent inhibitors of a number of zinc metalloproteins including Cys2His2 zinc finger transcription factors. Inhibition by [Co(acacen)(L)2] + of the target protein is believed to occur through a dissociative exchange of the labile axial ligands for histidine (His) residues essential for function. Here, we report a series of spectroscopic investigations with model peptides of zinc fingers that elucidate the interaction between [Co(acacen)(L)2]+ complexes and zinc finger transcription factors. Observed changes in NMR chemical shifts and 2D 1H- 1H NOESY NMR spectra demonstrate the preference of [Co(acacen)(L)2]+ complexes to coordinate His residues over other amino acids. The conformation of [Co(acacen)(L)2] + upon His coordination was characterized by 1H NMR spectroscopy, near-UV CD, and electronic absorption. These studies reveal that the resulting His-coordinated [Co(acacen)(L)2]+ complex possesses an octahedral structure. The effects of [Co(acacen)(L) 2]+ complexes on the zinc-finger structure were assessed by the degree of hydrogen bonding (probed by 2D NMR spectroscopy) and secondary-structure profiles measured by far-UV CD. These structural studies demonstrate the ability of [Co(acacen)(L)2]+ complexes to disrupt the ββα structure of zinc fingers, resulting in primarily random-coil conformations. A mechanism is described wherein [Co(acacen)(L)2]+ complexes inhibit zinc finger transcription factor activity through selectively coordinating His residues in the zinc finger by dissociative ligand exchange and disrupting the ββα structural motif required for gene regulation. Uncrossing fingers: Transition-metal complexes are emerging as promising zinc finger transcription factor inhibitors (see scheme). The dynamic structure of zinc fingers can make inhibition difficult to characterize. An array of spectroscopic studies is described to elucidate the specific interaction between cobalt(III) complexes and zinc-finger peptides.",
keywords = "cobalt, Schiff bases, spectroscopy, transcription factors, zinc fingers",
author = "Marie Heffern and Kurutz, {Josh W.} and Meade, {Thomas J.}",
year = "2013",
month = "12",
day = "9",
doi = "10.1002/chem.201301659",
language = "English (US)",
volume = "19",
pages = "17043--17053",
journal = "Chemistry - A European Journal",
issn = "0947-6539",
publisher = "Wiley-VCH Verlag",
number = "50",

}

TY - JOUR

T1 - Spectroscopic elucidation of the inhibitory mechanism of Cys 2His2 zinc finger transcription factors by cobalt(III) schiff base complexes

AU - Heffern, Marie

AU - Kurutz, Josh W.

AU - Meade, Thomas J.

PY - 2013/12/9

Y1 - 2013/12/9

N2 - Transcription factors are key regulators in both normal and pathological cell processes. Affecting the activity of these proteins is a promising strategy for understanding gene regulation and developing effective therapeutics. CoIII Schiff base complexes ([Co(acacen)(L)2]+ where L=labile axial ligands) have been shown to be potent inhibitors of a number of zinc metalloproteins including Cys2His2 zinc finger transcription factors. Inhibition by [Co(acacen)(L)2] + of the target protein is believed to occur through a dissociative exchange of the labile axial ligands for histidine (His) residues essential for function. Here, we report a series of spectroscopic investigations with model peptides of zinc fingers that elucidate the interaction between [Co(acacen)(L)2]+ complexes and zinc finger transcription factors. Observed changes in NMR chemical shifts and 2D 1H- 1H NOESY NMR spectra demonstrate the preference of [Co(acacen)(L)2]+ complexes to coordinate His residues over other amino acids. The conformation of [Co(acacen)(L)2] + upon His coordination was characterized by 1H NMR spectroscopy, near-UV CD, and electronic absorption. These studies reveal that the resulting His-coordinated [Co(acacen)(L)2]+ complex possesses an octahedral structure. The effects of [Co(acacen)(L) 2]+ complexes on the zinc-finger structure were assessed by the degree of hydrogen bonding (probed by 2D NMR spectroscopy) and secondary-structure profiles measured by far-UV CD. These structural studies demonstrate the ability of [Co(acacen)(L)2]+ complexes to disrupt the ββα structure of zinc fingers, resulting in primarily random-coil conformations. A mechanism is described wherein [Co(acacen)(L)2]+ complexes inhibit zinc finger transcription factor activity through selectively coordinating His residues in the zinc finger by dissociative ligand exchange and disrupting the ββα structural motif required for gene regulation. Uncrossing fingers: Transition-metal complexes are emerging as promising zinc finger transcription factor inhibitors (see scheme). The dynamic structure of zinc fingers can make inhibition difficult to characterize. An array of spectroscopic studies is described to elucidate the specific interaction between cobalt(III) complexes and zinc-finger peptides.

AB - Transcription factors are key regulators in both normal and pathological cell processes. Affecting the activity of these proteins is a promising strategy for understanding gene regulation and developing effective therapeutics. CoIII Schiff base complexes ([Co(acacen)(L)2]+ where L=labile axial ligands) have been shown to be potent inhibitors of a number of zinc metalloproteins including Cys2His2 zinc finger transcription factors. Inhibition by [Co(acacen)(L)2] + of the target protein is believed to occur through a dissociative exchange of the labile axial ligands for histidine (His) residues essential for function. Here, we report a series of spectroscopic investigations with model peptides of zinc fingers that elucidate the interaction between [Co(acacen)(L)2]+ complexes and zinc finger transcription factors. Observed changes in NMR chemical shifts and 2D 1H- 1H NOESY NMR spectra demonstrate the preference of [Co(acacen)(L)2]+ complexes to coordinate His residues over other amino acids. The conformation of [Co(acacen)(L)2] + upon His coordination was characterized by 1H NMR spectroscopy, near-UV CD, and electronic absorption. These studies reveal that the resulting His-coordinated [Co(acacen)(L)2]+ complex possesses an octahedral structure. The effects of [Co(acacen)(L) 2]+ complexes on the zinc-finger structure were assessed by the degree of hydrogen bonding (probed by 2D NMR spectroscopy) and secondary-structure profiles measured by far-UV CD. These structural studies demonstrate the ability of [Co(acacen)(L)2]+ complexes to disrupt the ββα structure of zinc fingers, resulting in primarily random-coil conformations. A mechanism is described wherein [Co(acacen)(L)2]+ complexes inhibit zinc finger transcription factor activity through selectively coordinating His residues in the zinc finger by dissociative ligand exchange and disrupting the ββα structural motif required for gene regulation. Uncrossing fingers: Transition-metal complexes are emerging as promising zinc finger transcription factor inhibitors (see scheme). The dynamic structure of zinc fingers can make inhibition difficult to characterize. An array of spectroscopic studies is described to elucidate the specific interaction between cobalt(III) complexes and zinc-finger peptides.

KW - cobalt

KW - Schiff bases

KW - spectroscopy

KW - transcription factors

KW - zinc fingers

UR - http://www.scopus.com/inward/record.url?scp=84889595075&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84889595075&partnerID=8YFLogxK

U2 - 10.1002/chem.201301659

DO - 10.1002/chem.201301659

M3 - Article

VL - 19

SP - 17043

EP - 17053

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

SN - 0947-6539

IS - 50

ER -