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Heterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam

Author

Listed:
  • Tek Narsingh Malla

    (University of Wisconsin-Milwaukee)

  • Kara Zielinski

    (Cornell University)

  • Luis Aldama

    (Northeastern Illinois University)

  • Sasa Bajt

    (The Hamburg Centre for Ultrafast Imaging
    Center for Free-Electron Laser Science CFEL, Deutsches Elektronen Synchrotron)

  • Denisse Feliz

    (Northeastern Illinois University)

  • Brendon Hayes

    (Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory)

  • Mark Hunter

    (Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory)

  • Christopher Kupitz

    (Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory)

  • Stella Lisova

    (Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory)

  • Juraj Knoska

    (Center for Free-Electron Laser Science CFEL, Deutsches Elektronen Synchrotron)

  • Jose Manuel Martin-Garcia

    (Spanish National Research Council (CSIC))

  • Valerio Mariani

    (Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory)

  • Suraj Pandey

    (University of Wisconsin-Milwaukee)

  • Ishwor Poudyal

    (University of Wisconsin-Milwaukee)

  • Raymond G. Sierra

    (Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory)

  • Alexandra Tolstikova

    (Deutsches Elektronen-Synchrotron DESY)

  • Oleksandr Yefanov

    (Center for Free-Electron Laser Science CFEL, Deutsches Elektronen Synchrotron)

  • Chung Hong Yoon

    (Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory)

  • Abbas Ourmazd

    (University of Wisconsin-Milwaukee)

  • Petra Fromme

    (20 Arizona State University)

  • Peter Schwander

    (University of Wisconsin-Milwaukee)

  • Anton Barty

    (Deutsches Elektronen-Synchrotron DESY
    Center for Data and Computing in Natural Science CDCS, Deutsches Elektronen-Synchrotron DESY)

  • Henry N. Chapman

    (The Hamburg Centre for Ultrafast Imaging
    Center for Free-Electron Laser Science CFEL, Deutsches Elektronen Synchrotron
    Universität Hamburg)

  • Emina A. Stojkovic

    (Northeastern Illinois University)

  • Alexander Batyuk

    (Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory)

  • Sébastien Boutet

    (Linac Coherent Light Source LCLS, SLAC National Accelerator Laboratory)

  • George N. Phillips

    (Rice University
    Rice University)

  • Lois Pollack

    (Cornell University)

  • Marius Schmidt

    (University of Wisconsin-Milwaukee)

Abstract

For decades, researchers have elucidated essential enzymatic functions on the atomic length scale by tracing atomic positions in real-time. Our work builds on possibilities unleashed by mix-and-inject serial crystallography (MISC) at X-ray free electron laser facilities. In this approach, enzymatic reactions are triggered by mixing substrate or ligand solutions with enzyme microcrystals. Here, we report in atomic detail (between 2.2 and 2.7 Å resolution) by room-temperature, time-resolved crystallography with millisecond time-resolution (with timepoints between 3 ms and 700 ms) how the Mycobacterium tuberculosis enzyme BlaC is inhibited by sulbactam (SUB). Our results reveal ligand binding heterogeneity, ligand gating, cooperativity, induced fit, and conformational selection all from the same set of MISC data, detailing how SUB approaches the catalytic clefts and binds to the enzyme noncovalently before reacting to a trans-enamine. This was made possible in part by the application of singular value decomposition to the MISC data using a program that remains functional even if unit cell parameters change up to 3 Å during the reaction.

Suggested Citation

  • Tek Narsingh Malla & Kara Zielinski & Luis Aldama & Sasa Bajt & Denisse Feliz & Brendon Hayes & Mark Hunter & Christopher Kupitz & Stella Lisova & Juraj Knoska & Jose Manuel Martin-Garcia & Valerio Ma, 2023. "Heterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41246-1
    DOI: 10.1038/s41467-023-41246-1
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    References listed on IDEAS

    as
    1. M. Wilamowski & D. A. Sherrell & Y. Kim & A. Lavens & R. W. Henning & K. Lazarski & A. Shigemoto & M. Endres & N. Maltseva & G. Babnigg & S. C. Burdette & V. Srajer & A. Joachimiak, 2022. "Time-resolved β-lactam cleavage by L1 metallo-β-lactamase," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. J. R. Stagno & Y. Liu & Y. R. Bhandari & C. E. Conrad & S. Panja & M. Swain & L. Fan & G. Nelson & C. Li & D. R. Wendel & T. A. White & J. D. Coe & M. O. Wiedorn & J. Knoska & D. Oberthuer & R. A. Tuc, 2017. "Structures of riboswitch RNA reaction states by mix-and-inject XFEL serial crystallography," Nature, Nature, vol. 541(7636), pages 242-246, January.
    3. Shiou-Ru Tzeng & Charalampos G. Kalodimos, 2012. "Protein activity regulation by conformational entropy," Nature, Nature, vol. 488(7410), pages 236-240, August.
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