Bridging the maytansine and vinca sites: cryptophycins target beta-tubulin's T5-loop
Abel A-C, Mühlethaler T, Dessin C, Schachtsiek T, Sammet B, Sharpe T, Steinmetz MO, Sewald N, Prota AE (2024)
Journal of Biological Chemistry: 107363.
Zeitschriftenaufsatz
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Autor*in
Abel, Anne-Catherine;
Mühlethaler, Tobias;
Dessin, CedricUniBi;
Schachtsiek, ThomasUniBi;
Sammet, BenediktUniBi;
Sharpe, Timothy;
Steinmetz, Michel O;
Sewald, NorbertUniBi ;
Prota, Andrea E
Einrichtung
Abstract / Bemerkung
Cryptophycins are microtubule-targeting agents (MTAs) that belong to the most potent antimitotic compounds known to date; however, their exact molecular mechanism of action remains unclear. Here, we present the 2.2 A resolution X-ray crystal structure of a potent cryptophycin derivative bound to the alphabeta-tubulin heterodimer. The structure addresses conformational issues present in a previous 3.3 A resolution cryo-electron microscopy structure of cryptophycin-52 bound to the maytansine site of beta-tubulin. It further provides atomic details on interactions of cryptophycins, which had not been described previously, including ones that are in line with structure-activity relationship (SAR) studies. Interestingly, we discovered a second cryptophycin-binding site that involves the T5-loop of beta-tubulin, a critical secondary structure element involved in the exchange of the guanosine nucleotide and in the formation of longitudinal tubulin contacts in microtubules. Cryptophycins are the first natural ligands found to bind to this new "betaT5-loop site" that bridges the maytansine and vinca sites. Our results offer unique avenues to rationally design novel MTAs with the capacity to modulate T5-loop dynamics and to simultaneously engage multiple beta-tubulin binding sites. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.
Erscheinungsjahr
2024
Zeitschriftentitel
Journal of Biological Chemistry
Art.-Nr.
107363
eISSN
1083-351X
Page URI
https://pub.uni-bielefeld.de/record/2989902
Zitieren
Abel A-C, Mühlethaler T, Dessin C, et al. Bridging the maytansine and vinca sites: cryptophycins target beta-tubulin's T5-loop. Journal of Biological Chemistry. 2024: 107363.
Abel, A. - C., Mühlethaler, T., Dessin, C., Schachtsiek, T., Sammet, B., Sharpe, T., Steinmetz, M. O., et al. (2024). Bridging the maytansine and vinca sites: cryptophycins target beta-tubulin's T5-loop. Journal of Biological Chemistry, 107363. https://doi.org/10.1016/j.jbc.2024.107363
Abel, Anne-Catherine, Mühlethaler, Tobias, Dessin, Cedric, Schachtsiek, Thomas, Sammet, Benedikt, Sharpe, Timothy, Steinmetz, Michel O, Sewald, Norbert, and Prota, Andrea E. 2024. “Bridging the maytansine and vinca sites: cryptophycins target beta-tubulin's T5-loop”. Journal of Biological Chemistry: 107363.
Abel, A. - C., Mühlethaler, T., Dessin, C., Schachtsiek, T., Sammet, B., Sharpe, T., Steinmetz, M. O., Sewald, N., and Prota, A. E. (2024). Bridging the maytansine and vinca sites: cryptophycins target beta-tubulin's T5-loop. Journal of Biological Chemistry:107363.
Abel, A.-C., et al., 2024. Bridging the maytansine and vinca sites: cryptophycins target beta-tubulin's T5-loop. Journal of Biological Chemistry, : 107363.
A.-C. Abel, et al., “Bridging the maytansine and vinca sites: cryptophycins target beta-tubulin's T5-loop”, Journal of Biological Chemistry, 2024, : 107363.
Abel, A.-C., Mühlethaler, T., Dessin, C., Schachtsiek, T., Sammet, B., Sharpe, T., Steinmetz, M.O., Sewald, N., Prota, A.E.: Bridging the maytansine and vinca sites: cryptophycins target beta-tubulin's T5-loop. Journal of Biological Chemistry. : 107363 (2024).
Abel, Anne-Catherine, Mühlethaler, Tobias, Dessin, Cedric, Schachtsiek, Thomas, Sammet, Benedikt, Sharpe, Timothy, Steinmetz, Michel O, Sewald, Norbert, and Prota, Andrea E. “Bridging the maytansine and vinca sites: cryptophycins target beta-tubulin's T5-loop”. Journal of Biological Chemistry (2024): 107363.
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