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A nucleotide-sensing oligomerization mechanism that controls NrdR-dependent transcription of ribonucleotide reductases

Rozman Grinberg, Inna ; Martínez-Carranza, Markel LU ; Bimai, Ornella ; Nouaïria, Ghada ; Shahid, Saher ; Lundin, Daniel ; Logan, Derek T LU orcid ; Sjöberg, Britt-Marie and Stenmark, Pål LU orcid (2022) In Nature Communications 13.
Abstract

Ribonucleotide reductase (RNR) is an essential enzyme that catalyzes the synthesis of DNA building blocks in virtually all living cells. NrdR, an RNR-specific repressor, controls the transcription of RNR genes and, often, its own, in most bacteria and some archaea. NrdR senses the concentration of nucleotides through its ATP-cone, an evolutionarily mobile domain that also regulates the enzymatic activity of many RNRs, while a Zn-ribbon domain mediates binding to NrdR boxes upstream of and overlapping the transcription start site of RNR genes. Here, we combine biochemical and cryo-EM studies of NrdR from Streptomyces coelicolor to show, at atomic resolution, how NrdR binds to DNA. The suggested mechanism involves an initial dodecamer... (More)

Ribonucleotide reductase (RNR) is an essential enzyme that catalyzes the synthesis of DNA building blocks in virtually all living cells. NrdR, an RNR-specific repressor, controls the transcription of RNR genes and, often, its own, in most bacteria and some archaea. NrdR senses the concentration of nucleotides through its ATP-cone, an evolutionarily mobile domain that also regulates the enzymatic activity of many RNRs, while a Zn-ribbon domain mediates binding to NrdR boxes upstream of and overlapping the transcription start site of RNR genes. Here, we combine biochemical and cryo-EM studies of NrdR from Streptomyces coelicolor to show, at atomic resolution, how NrdR binds to DNA. The suggested mechanism involves an initial dodecamer loaded with two ATP molecules that cannot bind to DNA. When dATP concentrations increase, an octamer forms that is loaded with one molecule each of dATP and ATP per monomer. A tetramer derived from this octamer then binds to DNA and represses transcription of RNR. In many bacteria - including well-known pathogens such as Mycobacterium tuberculosis - NrdR simultaneously controls multiple RNRs and hence DNA synthesis, making it an excellent target for novel antibiotics development.

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Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adenosine Triphosphate/metabolism, Cryoelectron Microscopy, Gene Expression Regulation, Bacterial, Nucleotides/chemistry, Ribonucleotide Reductases/genetics, Streptomyces coelicolor/metabolism
in
Nature Communications
volume
13
article number
2700
pages
10 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:35577776
  • scopus:85130167658
ISSN
2041-1723
DOI
10.1038/s41467-022-30328-1
language
English
LU publication?
yes
additional info
© 2022. The Author(s).
id
4d732b92-989c-4681-871c-fef7b1344a3c
date added to LUP
2022-06-03 10:11:21
date last changed
2024-04-29 20:46:52
@article{4d732b92-989c-4681-871c-fef7b1344a3c,
  abstract     = {{<p>Ribonucleotide reductase (RNR) is an essential enzyme that catalyzes the synthesis of DNA building blocks in virtually all living cells. NrdR, an RNR-specific repressor, controls the transcription of RNR genes and, often, its own, in most bacteria and some archaea. NrdR senses the concentration of nucleotides through its ATP-cone, an evolutionarily mobile domain that also regulates the enzymatic activity of many RNRs, while a Zn-ribbon domain mediates binding to NrdR boxes upstream of and overlapping the transcription start site of RNR genes. Here, we combine biochemical and cryo-EM studies of NrdR from Streptomyces coelicolor to show, at atomic resolution, how NrdR binds to DNA. The suggested mechanism involves an initial dodecamer loaded with two ATP molecules that cannot bind to DNA. When dATP concentrations increase, an octamer forms that is loaded with one molecule each of dATP and ATP per monomer. A tetramer derived from this octamer then binds to DNA and represses transcription of RNR. In many bacteria - including well-known pathogens such as Mycobacterium tuberculosis - NrdR simultaneously controls multiple RNRs and hence DNA synthesis, making it an excellent target for novel antibiotics development.</p>}},
  author       = {{Rozman Grinberg, Inna and Martínez-Carranza, Markel and Bimai, Ornella and Nouaïria, Ghada and Shahid, Saher and Lundin, Daniel and Logan, Derek T and Sjöberg, Britt-Marie and Stenmark, Pål}},
  issn         = {{2041-1723}},
  keywords     = {{Adenosine Triphosphate/metabolism; Cryoelectron Microscopy; Gene Expression Regulation, Bacterial; Nucleotides/chemistry; Ribonucleotide Reductases/genetics; Streptomyces coelicolor/metabolism}},
  language     = {{eng}},
  month        = {{05}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{A nucleotide-sensing oligomerization mechanism that controls NrdR-dependent transcription of ribonucleotide reductases}},
  url          = {{http://dx.doi.org/10.1038/s41467-022-30328-1}},
  doi          = {{10.1038/s41467-022-30328-1}},
  volume       = {{13}},
  year         = {{2022}},
}