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

Maximilian Wranik, Tobias Weinert, Chavdar Slavov, Tiziana Masini, Antonia Furrer, Natacha Gaillard, Dario Gioia, Marco Ferrarotti, Daniel James, Hannah Glover, Melissa Carrillo, Demet Kekilli, Robin Stipp, Petr Skopintsev, Steffen Brünle, Tobias Mühlethaler, John Beale, Dardan Gashi, Karol Nass, Dmitry Ozerov, Philip J. M. Johnson, Claudio Cirelli, Camila Bacellar, Markus Braun, Meitian Wang, Florian Dworkowski, Chris Milne, Andrea Cavalli, Josef Wachtveitl, Michel O. Steinmetz () and Jörg Standfuss ()
Additional contact information
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
Josef Wachtveitl: Goethe University
Michel O. Steinmetz: Paul Scherrer Institut
Jörg Standfuss: Paul Scherrer Institut

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-36481-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36481-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-36481-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().