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Peer-reviewedCC BYNucleic acids research

Mechanism of NanR transcriptional activation of sialic acid metabolism in Streptococcus pneumoniae.

  • David M Wood1
  • Ashleigh S Johns1
  • Zachary D Tillett1
  • Heather L Shearer2
  • Santosh Panjikar3,4
  • Yee-Foong Mok5
  • Michael D W Griffin5
  • Timothy M Allison6
  • Rachel A North7
  • Paul E Pace2
  • Borries Demeler8,9
  • Mark B Hampton2
2 more authors
  • Renwick C J Dobson1,5
  • Christopher R Horne1,10,11,12
12 affiliations
  1. 1Biomolecular Interaction Centre and School of Biological Sciences, University of Canterbury, PO Box 4800, Christchurch 8140, New Zealand.
  2. 2Mātai Hāora-Centre for Redox Biology and Medicine, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch 8041, New Zealand.
  3. 3Australian Synchrotron, ANSTO, Clayton, 800 Blackburn Road, Victoria 3168, Australia.
  4. 4Department of Biochemistry and Molecular Biology, Monash University, Melbourne 3800 VIC, Australia.
  5. 5Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
  6. 6Biomolecular Interaction Centre, School of Physical and Chemical Sciences, University of Canterbury, Christchurch 8041, New Zealand.
  7. 7School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales 2006, Australia.
  8. 8Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada.
  9. 9Department of Chemistry and Biochemistry, University of Montana, Missoula, MT 59812, United States.
  10. 10Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia.
  11. 11Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.
  12. 12Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria 3052, Australia.
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Abstract

In Streptococcus pneumoniae, the RpiR transcriptional regulator NanR (SpNanR) senses sialic acid in the environment and upregulates transcription of the nan and sia A operons to increase uptake and metabolism of sialic acid. The molecular basis of this activation is unknown. Here, we demonstrate that SpNanR binds N-acetylmannosamine-6-phosphate, a metabolite of sialic acid catabolism. SpNanR exists in a dimer-tetramer equilibrium, and N-acetylmannosamine-6-phosphate binding strongly stabilizes the tetramer. Crystal structures and site-specific substitutions demonstrate that N-acetylmannosamine-6-phosphate bridges and stabilizes the SpNanR tetramer. SpNanR binds its DNA recognition sequence with nanomolar affinity. Notably, the effector N-acetylmannosamine-6-phosphate does not affect the affinity of SpNanR for DNA. The DNA-binding domains are not structurally coupled to the sugar isomerase domains, explaining why N-acetylmannosamine-6-phosphate binding does not affect DNA binding. Structural analysis reveals that sequence specificity arises through distortion of B-DNA and an unusual π-stack formed by two arginine residues in the minor groove, while affinity is driven by backbone contacts. We propose a mechanism by which S. pneumoniae regulates sialic acid metabolism, consistent with our biophysical experiments and in vivo regulatory behavior. These findings define a unique activation mechanism for an RpiR regulator and provide new insights into carbohydrate-responsive gene regulation in pneumococci.

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Cite

BibTeXRIS
BibTeX
@article{wood2026mechanism,
  title = {{Mechanism of NanR transcriptional activation of sialic acid metabolism in Streptococcus pneumoniae.}},
  author = {David M Wood and Ashleigh S Johns and Zachary D Tillett and Heather L Shearer and Santosh Panjikar and Yee-Foong Mok and Michael D W Griffin and Timothy M Allison and Rachel A North and Paul E Pace and Borries Demeler and Mark B Hampton and Renwick C J Dobson and Christopher R Horne},
  journal = {Nucleic acids research},
  year = {2026},
  month = sep,
  doi = {10.1093/nar/gkag953},
  url = {https://europepmc.org/article/MED/42831430},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Mechanism of NanR transcriptional activation of sialic acid metabolism in Streptococcus pneumoniae.
AU  - David M Wood
AU  - Ashleigh S Johns
AU  - Zachary D Tillett
AU  - Heather L Shearer
AU  - Santosh Panjikar
AU  - Yee-Foong Mok
AU  - Michael D W Griffin
AU  - Timothy M Allison
AU  - Rachel A North
AU  - Paul E Pace
AU  - Borries Demeler
AU  - Mark B Hampton
AU  - Renwick C J Dobson
AU  - Christopher R Horne
PY  - 2026
DA  - 2026/09/01
JO  - Nucleic acids research
DO  - 10.1093/nar/gkag953
UR  - https://europepmc.org/article/MED/42831430
AB  - In Streptococcus pneumoniae, the RpiR transcriptional regulator NanR (SpNanR) senses sialic acid in the environment and upregulates transcription of the nan and sia A operons to increase uptake and metabolism of sialic acid. The molecular basis of this activation is unknown. Here, we demonstrate that SpNanR binds N-acetylmannosamine-6-phosphate, a metabolite of sialic acid catabolism. SpNanR exists in a dimer-tetramer equilibrium, and N-acetylmannosamine-6-phosphate binding strongly stabilizes the tetramer. Crystal structures and site-specific substitutions demonstrate that N-acetylmannosamine-6-phosphate bridges and stabilizes the SpNanR tetramer. SpNanR binds its DNA recognition sequence with nanomolar affinity. Notably, the effector N-acetylmannosamine-6-phosphate does not affect the affinity of SpNanR for DNA. The DNA-binding domains are not structurally coupled to the sugar isomerase domains, explaining why N-acetylmannosamine-6-phosphate binding does not affect DNA binding. Structural analysis reveals that sequence specificity arises through distortion of B-DNA and an unusual π-stack formed by two arginine residues in the minor groove, while affinity is driven by backbone contacts. We propose a mechanism by which S. pneumoniae regulates sialic acid metabolism, consistent with our biophysical experiments and in vivo regulatory behavior. These findings define a unique activation mechanism for an RpiR regulator and provide new insights into carbohydrate-responsive gene regulation in pneumococci.
SN  - 0305-1048
SN  - 1362-4962
ER  -