bi7b00528_si_001.pdf (2.72 MB)
Redox-Specific Allosteric Modulation of the Conformational Dynamics of κB DNA by Pirin in the NF-κB Supramolecular Complex
journal contribution
posted on 2017-08-21, 00:00 authored by Charles Adeniran, Donald HamelbergThe
molecular basis of gene regulation by Nuclear Factor-κB
(NF-κB) transcription factors and their coregulators is not
well understood. This family of transcription factors controls a number
of essential subcellular processes. Human Pirin, a nonheme iron (Fe)
binding protein, has been shown to modulate the binding affinity between
p65 homodimeric NF-κB and κB DNA. However, the allosteric
effect of the active Fe(III) form of Pirin on the DNA has not been
established. Here, we use multiple microsecond-long molecular dynamics
simulations to explore the conformational dynamics of the free DNA,
the p65–DNA complex, and the Pirin–p65–DNA supramolecular
complex. We show that only the Fe(III) form of Pirin enhances the
affinity between p65 and the DNA in the Pirin–p65–DNA
supramolecular complex, in agreement with experiments. Additionally,
the results provide atomistic details of the effect of the active
Fe(III) form of Pirin on the DNA upon binding to the p65–DNA
complex. In general, unlike the Fe(II) form of Pirin, binding of the
Fe(III) form of Pirin to the p65–DNA complex significantly
alters both the conformational dynamics of the DNA and the interactions
between p65 and the DNA. The results provide atomic level understanding
of the modulation of the DNA as a result of a redox-specific Fe(II)/Fe(III)
coregulation of NF-κB by Pirin, knowledge that is necessary
to fully understand normal and aberrant subcellular processes and
the role of a subtle single electron redox process in gene regulation.