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In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors

Author

Listed:
  • Karol Nass

    (Deutsches Elektronen-Synchrotron DESY
    Paul Scherrer Institute (PSI))

  • Lars Redecke

    (University of Hamburg, and Institute of Biochemistry, University of Lübeck, at Deutsches Elektronen-Synchrotron (DESY)
    University of Lübeck
    University of Lübeck
    Photon Science)

  • M. Perbandt

    (University of Hamburg, at Deutsches Elektronen-Synchrotron (DESY)
    The Hamburg Centre for Ultrafast Imaging (CUI))

  • O. Yefanov

    (Deutsches Elektronen-Synchrotron DESY)

  • M. Klinge

    (University of Hamburg, and Institute of Biochemistry, University of Lübeck, at Deutsches Elektronen-Synchrotron (DESY)
    BioAgilytix Europe GmbH)

  • R. Koopmann

    (University of Tübingen)

  • F. Stellato

    (Deutsches Elektronen-Synchrotron DESY
    Università di Roma Tor Vergata and INFN)

  • A. Gabdulkhakov

    (Russian Academy of Sciences)

  • R. Schönherr

    (University of Lübeck
    Deutsches Elektronen Synchrotron (DESY), Photon Science)

  • D. Rehders

    (University of Hamburg, and Institute of Biochemistry, University of Lübeck, at Deutsches Elektronen-Synchrotron (DESY)
    BODE Chemie GmbH)

  • J. M. Lahey-Rudolph

    (Deutsches Elektronen-Synchrotron DESY
    University of Lübeck)

  • A. Aquila

    (Deutsches Elektronen-Synchrotron DESY
    LCLS, SLAC National Accelerator Laboratory)

  • A. Barty

    (Deutsches Elektronen-Synchrotron DESY)

  • S. Basu

    (Arizona State University
    Grenoble Outstation)

  • R. B. Doak

    (Arizona State University
    Max Planck Institute for Medical Research)

  • R. Duden

    (University of Lübeck)

  • M. Frank

    (Lawrence Livermore National Laboratory)

  • R. Fromme

    (Arizona State University)

  • S. Kassemeyer

    (Max-Planck-Institute for Medical Research)

  • G. Katona

    (University of Gothenburg)

  • R. Kirian

    (Arizona State University)

  • H. Liu

    (Arizona State University
    Complex Systems Division, Beijing Computational Science Research Center)

  • I. Majoul

    (University of Lübeck)

  • J. M. Martin-Garcia

    (Arizona State University)

  • M. Messerschmidt

    (LCLS, SLAC National Accelerator Laboratory
    Arizona State University)

  • R. L. Shoeman

    (Max-Planck-Institute for Medical Research)

  • U. Weierstall

    (Arizona State University)

  • S. Westenhoff

    (University of Gothenburg)

  • T. A. White

    (Deutsches Elektronen-Synchrotron DESY)

  • G. J. Williams

    (LCLS, SLAC National Accelerator Laboratory
    Brookhaven National Laboratory (BNL))

  • C. H. Yoon

    (Deutsches Elektronen-Synchrotron DESY
    LCLS, SLAC National Accelerator Laboratory)

  • N. Zatsepin

    (Arizona State University
    La Trobe University)

  • P. Fromme

    (Arizona State University)

  • M. Duszenko

    (University of Tübingen)

  • H. N. Chapman

    (Deutsches Elektronen-Synchrotron DESY
    The Hamburg Centre for Ultrafast Imaging (CUI)
    University of Hamburg)

  • C. Betzel

    (University of Hamburg, at Deutsches Elektronen-Synchrotron (DESY)
    The Hamburg Centre for Ultrafast Imaging (CUI))

Abstract

Sleeping sickness is a fatal disease caused by the protozoan parasite Trypanosoma brucei (Tb). Inosine-5’-monophosphate dehydrogenase (IMPDH) has been proposed as a potential drug target, since it maintains the balance between guanylate deoxynucleotide and ribonucleotide levels that is pivotal for the parasite. Here we report the structure of TbIMPDH at room temperature utilizing free-electron laser radiation on crystals grown in living insect cells. The 2.80 Å resolution structure reveals the presence of ATP and GMP at the canonical sites of the Bateman domains, the latter in a so far unknown coordination mode. Consistent with previously reported IMPDH complexes harboring guanosine nucleotides at the second canonical site, TbIMPDH forms a compact oligomer structure, supporting a nucleotide-controlled conformational switch that allosterically modulates the catalytic activity. The oligomeric TbIMPDH structure we present here reveals the potential of in cellulo crystallization to identify genuine allosteric co-factors from a natural reservoir of specific compounds.

Suggested Citation

  • Karol Nass & Lars Redecke & M. Perbandt & O. Yefanov & M. Klinge & R. Koopmann & F. Stellato & A. Gabdulkhakov & R. Schönherr & D. Rehders & J. M. Lahey-Rudolph & A. Aquila & A. Barty & S. Basu & R. B, 2020. "In cellulo crystallization of Trypanosoma brucei IMP dehydrogenase enables the identification of genuine co-factors," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14484-w
    DOI: 10.1038/s41467-020-14484-w
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    Cited by:

    1. Robert Schönherr & Juliane Boger & J. Mia Lahey-Rudolph & Mareike Harms & Jacqueline Kaiser & Sophie Nachtschatt & Marla Wobbe & Rainer Duden & Peter König & Gleb Bourenkov & Thomas R. Schneider & Lar, 2024. "A streamlined approach to structure elucidation using in cellulo crystallized recombinant proteins, InCellCryst," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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