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Uncoupling conformational states from activity in an allosteric enzyme

Author

Listed:
  • João P. Pisco

    (The Francis Crick Institute)

  • Cesira de Chiara

    (The Francis Crick Institute)

  • Kamila J. Pacholarz

    (University of Manchester)

  • Acely Garza-Garcia

    (The Francis Crick Institute)

  • Roksana W. Ogrodowicz

    (The Francis Crick Institute)

  • Philip A. Walker

    (The Francis Crick Institute)

  • Perdita E. Barran

    (University of Manchester)

  • Stephen J. Smerdon

    (The Francis Crick Institute)

  • Luiz Pedro S. de Carvalho

    (The Francis Crick Institute)

Abstract

ATP-phosphoribosyltransferase (ATP-PRT) is a hexameric enzyme in conformational equilibrium between an open and seemingly active state and a closed and presumably inhibited form. The structure-function relationship of allosteric regulation in this system is still not fully understood. Here, we develop a screening strategy for modulators of ATP-PRT and identify 3-(2-thienyl)-l-alanine (TIH) as an allosteric activator of this enzyme. Kinetic analysis reveals co-occupancy of the allosteric sites by TIH and l-histidine. Crystallographic and native ion-mobility mass spectrometry data show that the TIH-bound activated form of the enzyme closely resembles the inhibited l-histidine-bound closed conformation, revealing the uncoupling between ATP-PRT open and closed conformations and its functional state. These findings suggest that dynamic processes are responsible for ATP-PRT allosteric regulation and that similar mechanisms might also be found in other enzymes bearing a ferredoxin-like allosteric domain.

Suggested Citation

  • João P. Pisco & Cesira de Chiara & Kamila J. Pacholarz & Acely Garza-Garcia & Roksana W. Ogrodowicz & Philip A. Walker & Perdita E. Barran & Stephen J. Smerdon & Luiz Pedro S. de Carvalho, 2017. "Uncoupling conformational states from activity in an allosteric enzyme," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00224-0
    DOI: 10.1038/s41467-017-00224-0
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    Cited by:

    1. Gemma Fisher & Marina Corbella & Magnus S. Alphey & John Nicholson & Benjamin J. Read & Shina C. L. Kamerlin & Rafael G. da Silva, 2022. "Allosteric rescue of catalytically impaired ATP phosphoribosyltransferase variants links protein dynamics to active-site electrostatic preorganisation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Federica Maschietto & Uriel N. Morzan & Florentina Tofoleanu & Aria Gheeraert & Apala Chaudhuri & Gregory W. Kyro & Peter Nekrasov & Bernard Brooks & J. Patrick Loria & Ivan Rivalta & Victor S. Batist, 2023. "Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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