6QTN

Tubulin-cyclostreptin complex

Summary for 6QTN

• Entry DOI: 10.2210/pdb6qtn/pdb
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, Cyclostreptin, ... (14 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 6
• Total formula weight: 265671.68

Authors

Balaguer, F.d.A.,Muehlethaler, T.,Estevez-Gallego, J.,Calvo, E.,Gimenez-Abian, J.F.,Risinger, A.L.,Sorensen, E.J.,Vanderwal, C.D.,Altmann, K.-H.,Mooberry, S.L.,Steinmetz, M.O.,Oliva, M.A.,Prota, A.E.,Diaz, J.F. (deposition date: 2019-02-25, release date: 2019-04-03, Last modification date: 2024-01-24)

Primary citation

Balaguer, F.A.,Muhlethaler, T.,Estevez-Gallego, J.,Calvo, E.,Gimenez-Abian, J.F.,Risinger, A.L.,Sorensen, E.J.,Vanderwal, C.D.,Altmann, K.H.,Mooberry, S.L.,Steinmetz, M.O.,Oliva, M.A.,Prota, A.E.,Diaz, J.F.
Crystal Structure of the Cyclostreptin-Tubulin Adduct: Implications for Tubulin Activation by Taxane-Site Ligands.
Int J Mol Sci, 20:-, 2019

PubMed Abstract: It has been proposed that one of the mechanisms of taxane-site ligand-mediated tubulin activation is modulation of the structure of a switch element (the M-loop) from a disordered form in dimeric tubulin to a folded helical structure in microtubules. Here, we used covalent taxane-site ligands, including cyclostreptin, to gain further insight into this mechanism. The crystal structure of cyclostreptin-bound tubulin reveals covalent binding to βHis229, but no stabilization of the M-loop. The capacity of cyclostreptin to induce microtubule assembly compared to other covalent taxane-site agents demonstrates that the induction of tubulin assembly is not strictly dependent on M-loop stabilization. We further demonstrate that most covalent taxane-site ligands are able to partially overcome drug resistance mediated by βIII-tubulin (βIII) overexpression in HeLa cells, and compare their activities to pironetin, an interfacial covalent inhibitor of tubulin assembly that displays invariant growth inhibition in these cells. Our findings suggest a relationship between a diminished interaction of taxane-site ligands with βIII-tubulin and βIII tubulin-mediated drug resistance. This supports the idea that overexpression of βIII increases microtubule dynamicity by counteracting the enhanced microtubule stability promoted by covalent taxane-site binding ligands.

PubMed: 30897704
DOI: 10.3390/ijms20061392

Experimental method

X-RAY DIFFRACTION (1.9 Å)