5SB6

Tubulin-todalam-10-complex

Summary for 5SB6

• Entry DOI: 10.2210/pdb5sb6/pdb
• Group deposition: Todalam compounds complexed with T2R-TTL (G_1002214)
• Descriptor: Tubulin alpha-1B chain, N-{4-[2-(4-fluoroanilino)-1,3-thiazol-4-yl]phenyl}acetamide, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 6
• Total formula weight: 264873.74

Authors

Muehlethaler, T.,Milanos, L.,Ortega, J.A.,Blum, T.B.,Gioia, D.,Prota, A.E.,Cavalli, A.,Steinmetz, M.O. (deposition date: 2021-07-08, release date: 2022-04-27, Last modification date: 2024-05-22)

Primary citation

Muhlethaler, T.,Milanos, L.,Ortega, J.A.,Blum, T.B.,Gioia, D.,Roy, B.,Prota, A.E.,Cavalli, A.,Steinmetz, M.O.
Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action.
Angew.Chem.Int.Ed.Engl., 61:e202204052-e202204052, 2022

PubMed Abstract: In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. Todalam binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells in G2/M, induces cell death, and synergizes with vinblastine. The compound destabilizes microtubules by acting as a molecular plug that sterically inhibits the curved-to-straight conformational switch in the α-tubulin subunit, and by sequestering tubulin dimers into assembly incompetent oligomers. Our results describe for the first time the generation of a fully rationally designed small molecule tubulin inhibitor from a fragment, which displays a unique molecular mechanism of action. They thus demonstrate the usefulness of tubulin-binding fragments as valuable starting points for innovative antitubulin drug and chemical probe discovery campaigns.

PubMed: 35404502
DOI: 10.1002/anie.202204052

Experimental method

X-RAY DIFFRACTION (2.3 Å)