Allosteric histidine switch for regulation of intracellular zinc(II) fluctuation

Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):13661-13666. doi: 10.1073/pnas.1708563115. Epub 2017 Dec 11.


Metalloregulators allosterically control transcriptional activity through metal binding-induced reorganization of ligand residues and/or hydrogen bonding networks, while the coordination atoms on the same ligand residues remain seldom changed. Here we show that the MarR-type zinc transcriptional regulator ZitR switches one of its histidine nitrogen atoms for zinc coordination during the allosteric control of DNA binding. The Zn(II)-coordination nitrogen on histidine 42 within ZitR's high-affinity zinc site (site 1) switches from Nε2 to Nδ1 upon Zn(II) binding to its low-affinity zinc site (site 2), which facilitates ZitR's conversion from the nonoptimal to the optimal DNA-binding conformation. This histidine switch-mediated cooperation between site 1 and site 2 enables ZitR to adjust its DNA-binding affinity in response to a broad range of zinc fluctuation, which may allow the fine tuning of transcriptional regulation.

Keywords: X-ray crystallography; allostery; histidine switch; transcription factors; zinc homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Binding Sites
  • DNA / chemistry
  • DNA / metabolism
  • Histidine / chemistry*
  • Histidine / metabolism*
  • Intracellular Space / metabolism
  • Kinetics
  • Molecular Conformation
  • Structure-Activity Relationship
  • Zinc / metabolism*


  • Histidine
  • DNA
  • Zinc

Associated data

  • PDB/5YHX
  • PDB/5YI2
  • PDB/5YHY
  • PDB/5YI3
  • PDB/5YHZ
  • PDB/5YI0
  • PDB/5YI1