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Watching the release of a photopharmacological drug from tubulin using time-resolved serial crystallography

Author

Listed:
  • Maximilian Wranik

    (Paul Scherrer Institut)

  • Tobias Weinert

    (Paul Scherrer Institut)

  • Chavdar Slavov

    (Goethe University)

  • Tiziana Masini

    (Istituto Italiano di Tecnologia)

  • Antonia Furrer

    (Paul Scherrer Institut)

  • Natacha Gaillard

    (Paul Scherrer Institut)

  • Dario Gioia

    (Istituto Italiano di Tecnologia)

  • Marco Ferrarotti

    (Istituto Italiano di Tecnologia)

  • Daniel James

    (Paul Scherrer Institut)

  • Hannah Glover

    (Paul Scherrer Institut)

  • Melissa Carrillo

    (Paul Scherrer Institut)

  • Demet Kekilli

    (Paul Scherrer Institut)

  • Robin Stipp

    (Paul Scherrer Institut)

  • Petr Skopintsev

    (Paul Scherrer Institut)

  • Steffen Brünle

    (Paul Scherrer Institut)

  • Tobias Mühlethaler

    (Paul Scherrer Institut)

  • John Beale

    (Paul Scherrer Institut)

  • Dardan Gashi

    (Paul Scherrer Institut)

  • Karol Nass

    (Paul Scherrer Institut)

  • Dmitry Ozerov

    (Paul Scherrer Institut)

  • Philip J. M. Johnson

    (Paul Scherrer Institut)

  • Claudio Cirelli

    (Paul Scherrer Institut)

  • Camila Bacellar

    (Paul Scherrer Institut)

  • Markus Braun

    (Goethe University)

  • Meitian Wang

    (Paul Scherrer Institut)

  • Florian Dworkowski

    (Paul Scherrer Institut)

  • Chris Milne

    (Paul Scherrer Institut)

  • Andrea Cavalli

    (Istituto Italiano di Tecnologia
    University of Bologna)

  • Josef Wachtveitl

    (Goethe University)

  • Michel O. Steinmetz

    (Paul Scherrer Institut
    University of Basel)

  • Jörg Standfuss

    (Paul Scherrer Institut)

Abstract

The binding and release of ligands from their protein targets is central to fundamental biological processes as well as to drug discovery. Photopharmacology introduces chemical triggers that allow the changing of ligand affinities and thus biological activity by light. Insight into the molecular mechanisms of photopharmacology is largely missing because the relevant transitions during the light-triggered reaction cannot be resolved by conventional structural biology. Using time-resolved serial crystallography at a synchrotron and X-ray free-electron laser, we capture the release of the anti-cancer compound azo-combretastatin A4 and the resulting conformational changes in tubulin. Nine structural snapshots from 1 ns to 100 ms complemented by simulations show how cis-to-trans isomerization of the azobenzene bond leads to a switch in ligand affinity, opening of an exit channel, and collapse of the binding pocket upon ligand release. The resulting global backbone rearrangements are related to the action mechanism of microtubule-destabilizing drugs.

Suggested Citation

  • Maximilian Wranik & Tobias Weinert & Chavdar Slavov & Tiziana Masini & Antonia Furrer & Natacha Gaillard & Dario Gioia & Marco Ferrarotti & Daniel James & Hannah Glover & Melissa Carrillo & Demet Keki, 2023. "Watching the release of a photopharmacological drug from tubulin using time-resolved serial crystallography," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36481-5
    DOI: 10.1038/s41467-023-36481-5
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    References listed on IDEAS

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    1. Agata Butryn & Philipp S. Simon & Pierre Aller & Philip Hinchliffe & Ramzi N. Massad & Gabriel Leen & Catherine L. Tooke & Isabel Bogacz & In-Sik Kim & Asmit Bhowmick & Aaron S. Brewster & Nicholas E., 2021. "An on-demand, drop-on-drop method for studying enzyme catalysis by serial crystallography," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    2. Tobias Weinert & Natacha Olieric & Robert Cheng & Steffen Brünle & Daniel James & Dmitry Ozerov & Dardan Gashi & Laura Vera & May Marsh & Kathrin Jaeger & Florian Dworkowski & Ezequiel Panepucci & Shi, 2017. "Serial millisecond crystallography for routine room-temperature structure determination at synchrotrons," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
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    Cited by:

    1. Maximilian Wranik & Michal W. Kepa & Emma V. Beale & Daniel James & Quentin Bertrand & Tobias Weinert & Antonia Furrer & Hannah Glover & Dardan Gashi & Melissa Carrillo & Yasushi Kondo & Robin T. Stip, 2023. "A multi-reservoir extruder for time-resolved serial protein crystallography and compound screening at X-ray free-electron lasers," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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