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Mechanistic Insight into Conformational Control of Enzyme Activity by Genetically Encoded Metal-Responsive Switches.

Payal1, Jonathan Thirman2, Katherine A Edmonds1

  • 1Department of Chemistry, Indiana University, Bloomington, Indiana, USA.

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|April 25, 2026
PubMed
Summary
This summary is machine-generated.

Researchers engineered a metal-responsive protein system using bipyridylalanine (BpyAla). This system reversibly controls enzyme function by modulating localized conformational changes upon metal binding, offering a versatile platform for synthetic biology applications.

Keywords:
artificial metalloenzymeconformational switchingprolyl oligopeptidaseunnatural amino acid

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Area of Science:

  • Biochemistry
  • Synthetic Biology
  • Protein Engineering

Background:

  • Genetically encoded metal-responsive systems offer precise control over protein function.
  • Bipyridylalanine (BpyAla) residues enable metal chelation for reversible protein activity modulation.
  • Previous studies demonstrated the efficacy of BpyAla in distinct enzymes like Pfu POP and Pluc.

Purpose of the Study:

  • To investigate the mechanistic basis of metal-induced switching in Pyrococcus furiosus prolyl oligopeptidase (Pfu POP).
  • To quantify nickel(II) binding affinity and assess structural responses to Bpy2Ni(II) complex formation.
  • To elucidate how linking group-controlled conformational changes regulate enzyme activity.

Main Methods:

  • Fluorescence-based metal competition assays to determine Ni(II) binding affinity.
  • Molecular dynamics (MD) simulations to evaluate structural changes upon metal binding.
  • 19F NMR spectroscopy to probe conformational dynamics near the catalytic site.

Main Results:

  • Ni(II) binding affinity was quantified, revealing the strength of the metal-chelation interaction.
  • MD simulations and 19F NMR indicated metal binding induces conformational changes, particularly in the loop containing H592.
  • These localized conformational shifts near the catalytic triad were directly linked to enzyme activity modulation.

Conclusions:

  • Genetically encoded metal-binding motifs can regulate enzyme function via subtle, localized conformational changes.
  • This provides a versatile platform for engineering responsive protein systems.
  • Applications include synthetic biology, biosensing, and programmable catalysis.