7YZ6
Molecular snapshots of drug release from tubulin: Dark (steady state)
Summary for 7YZ6
| Entry DOI | 10.2210/pdb7yz6/pdb |
| Descriptor | Tubulin alpha-1B chain, Tubulin beta-2B chain, Designed Ankyrin Repeat Protein (DARPIN) D1, ... (8 entities in total) |
| Functional Keywords | time-resolved serial crystallography, tubulin dynamics, azobenzene dynamics, cell cycle |
| Biological source | synthetic construct More |
| Total number of polymer chains | 3 |
| Total formula weight | 119726.14 |
| Authors | Wranik, M.,Weinert, T.,Standfuss, J. (deposition date: 2022-02-18, release date: 2023-02-22, Last modification date: 2023-09-27) |
| Primary citation | 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 Cited by 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: 36807348DOI: 10.1038/s41467-023-36481-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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