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Bacterial transcriptional repressor NrdR – a flexible multifactorial nucleotide sensor

Rozman Grinberg, Inna ; Bimaï, Ornella ; Shahid, Saher ; Philipp, Lena ; Martínez-Carranza, Markel LU ; Banerjee, Ipsita LU ; Lundin, Daniel ; Stenmark, Pål LU orcid ; Sjöberg, Britt-Marie and Logan, Derek T. LU orcid (2025) In FEBS Journal
Abstract
NrdR is a bacterial transcriptional repressor consisting of a zinc
(Zn)-ribbon domain followed by an ATP-cone domain. Understanding its
mechanism of action could aid the design of novel antibacterials. NrdR
binds specifically to two “NrdR boxes” upstream of ribonucleotide
reductase operons, of which Escherichia coli has three: nrdHIEF, nrdDG and nrdAB, in the last of which we identified a new box. We show that E. coli
NrdR (EcoNrdR) has similar binding strength to all three sites when
loaded with ATP plus deoxyadenosine triphosphate (dATP) or equivalent
diphosphate combinations. No other combination of adenine nucleotides
promotes binding to DNA. We present crystal structures of
... (More)
NrdR is a bacterial transcriptional repressor consisting of a zinc
(Zn)-ribbon domain followed by an ATP-cone domain. Understanding its
mechanism of action could aid the design of novel antibacterials. NrdR
binds specifically to two “NrdR boxes” upstream of ribonucleotide
reductase operons, of which Escherichia coli has three: nrdHIEF, nrdDG and nrdAB, in the last of which we identified a new box. We show that E. coli
NrdR (EcoNrdR) has similar binding strength to all three sites when
loaded with ATP plus deoxyadenosine triphosphate (dATP) or equivalent
diphosphate combinations. No other combination of adenine nucleotides
promotes binding to DNA. We present crystal structures of
EcoNrdR–ATP–dATP and EcoNrdR–ADP–dATP, which are the first
high-resolution crystal structures of an NrdR. We have also determined
cryo-electron microscopy structures of DNA-bound EcoNrdR–ATP–dATP and
novel filaments of EcoNrdR–ATP. Tetrameric forms of EcoNrdR involve
alternating interactions between pairs of Zn-ribbon domains and
ATP-cones. The structures reveal considerable flexibility in relative
orientation of ATP-cones vs Zn-ribbon domains. The structure of
DNA-bound EcoNrdR–ATP–dATP shows that significant conformational
rearrangements between ATP-cones and Zn-ribbons accompany DNA binding
while the ATP-cones retain the same relative orientation. In contrast,
ATP-loaded EcoNrdR filaments show rearrangements of the ATP-cone pairs
and sequester the DNA-binding residues of NrdR such that they are unable
to bind to DNA. Our results, in combination with a previous structural
and biochemical study, point to highly flexible EcoNrdR structures that,
when loaded with the correct nucleotides, adapt to an optimal
promoter-binding conformation. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
ATP-cone, nucleotide binding, ribonucleotide reductase, transcription factor
in
FEBS Journal
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105000440394
  • pmid:40029022
ISSN
1742-464X
DOI
10.1111/febs.70037
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
id
1d69a03f-ea23-4e0f-9640-e267bef9eeb8
date added to LUP
2025-04-07 09:58:58
date last changed
2025-06-16 14:42:57
@article{1d69a03f-ea23-4e0f-9640-e267bef9eeb8,
  abstract     = {{NrdR is a bacterial transcriptional repressor consisting of a zinc <br>
(Zn)-ribbon domain followed by an ATP-cone domain. Understanding its <br>
mechanism of action could aid the design of novel antibacterials. NrdR <br>
binds specifically to two “NrdR boxes” upstream of ribonucleotide <br>
reductase operons, of which <i>Escherichia coli</i> has three: nrdHIEF, nrdDG and nrdAB, in the last of which we identified a new box. We show that <i>E. coli</i><br>
 NrdR (EcoNrdR) has similar binding strength to all three sites when <br>
loaded with ATP plus deoxyadenosine triphosphate (dATP) or equivalent <br>
diphosphate combinations. No other combination of adenine nucleotides <br>
promotes binding to DNA. We present crystal structures of <br>
EcoNrdR–ATP–dATP and EcoNrdR–ADP–dATP, which are the first <br>
high-resolution crystal structures of an NrdR. We have also determined <br>
cryo-electron microscopy structures of DNA-bound EcoNrdR–ATP–dATP and <br>
novel filaments of EcoNrdR–ATP. Tetrameric forms of EcoNrdR involve <br>
alternating interactions between pairs of Zn-ribbon domains and <br>
ATP-cones. The structures reveal considerable flexibility in relative <br>
orientation of ATP-cones vs Zn-ribbon domains. The structure of <br>
DNA-bound EcoNrdR–ATP–dATP shows that significant conformational <br>
rearrangements between ATP-cones and Zn-ribbons accompany DNA binding <br>
while the ATP-cones retain the same relative orientation. In contrast, <br>
ATP-loaded EcoNrdR filaments show rearrangements of the ATP-cone pairs <br>
and sequester the DNA-binding residues of NrdR such that they are unable<br>
 to bind to DNA. Our results, in combination with a previous structural <br>
and biochemical study, point to highly flexible EcoNrdR structures that,<br>
 when loaded with the correct nucleotides, adapt to an optimal <br>
promoter-binding conformation.}},
  author       = {{Rozman Grinberg, Inna and Bimaï, Ornella and Shahid, Saher and Philipp, Lena and Martínez-Carranza, Markel and Banerjee, Ipsita and Lundin, Daniel and Stenmark, Pål and Sjöberg, Britt-Marie and Logan, Derek T.}},
  issn         = {{1742-464X}},
  keywords     = {{ATP-cone; nucleotide binding; ribonucleotide reductase; transcription factor}},
  language     = {{eng}},
  month        = {{03}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{FEBS Journal}},
  title        = {{Bacterial transcriptional repressor NrdR – a flexible multifactorial nucleotide sensor}},
  url          = {{http://dx.doi.org/10.1111/febs.70037}},
  doi          = {{10.1111/febs.70037}},
  year         = {{2025}},
}