7YZ2

Molecular snapshots of drug release from tubulin: 10 milliseconds after photoactivation.

7YZ2 の概要

• エントリーDOI: 10.2210/pdb7yz2/pdb
• 分子名称: Tubulin alpha-1B chain, Tubulin beta-2B chain, Designed Ankyrin Repeat Protein (DARPIN) D1, ... (7 entities in total)
• 機能のキーワード: time-resolved serial crystallography, tubulin dynamics, azobenzene dynamics, cell cycle
• 由来する生物種: synthetic construct; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 119263.46

構造登録者

Wranik, M.,Weinert, T.,Standfuss, J. (登録日: 2022-02-18, 公開日: 2023-02-22, 最終更新日: 2024-02-07)

主引用文献

Wranik, M.,Weinert, T.,Slavov, C.,Masini, T.,Furrer, A.,Gaillard, N.,Gioia, D.,Ferrarotti, M.,James, D.,Glover, H.,Carrillo, M.,Kekilli, D.,Stipp, R.,Skopintsev, P.,Brunle, S.,Muhlethaler, T.,Beale, J.,Gashi, D.,Nass, K.,Ozerov, D.,Johnson, P.J.M.,Cirelli, C.,Bacellar, C.,Braun, M.,Wang, M.,Dworkowski, F.,Milne, C.,Cavalli, A.,Wachtveitl, J.,Steinmetz, M.O.,Standfuss, J.
Watching the release of a photopharmacological drug from tubulin using time-resolved serial crystallography.
Nat Commun, 14:903-903, 2023

PubMed 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.

PubMed: 36807348
DOI: 10.1038/s41467-023-36481-5

実験手法

X-RAY DIFFRACTION (2.2 Å)