Bridging the maytansine and vinca sites: Cryptophycins target β-tubulin's T5-loop.

Autor:	Abel AC; Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland; Biozentrum, University of Basel, Basel, Switzerland., Mühlethaler T; Biozentrum, University of Basel, Basel, Switzerland., Dessin C; Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, Germany., Schachtsiek T; Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, Germany., Sammet B; Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, Germany., Sharpe T; Biozentrum, University of Basel, Basel, Switzerland., Steinmetz MO; Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland; Biozentrum, University of Basel, Basel, Switzerland., Sewald N; Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Bielefeld, Germany. Electronic address: norbert.sewald@uni-bielefeld.de., Prota AE; Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland. Electronic address: andrea.prota@psi.ch.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Jun; Vol. 300 (6), pp. 107363. Date of Electronic Publication: 2024 May 10.
DOI:	10.1016/j.jbc.2024.107363
Abstrakt:	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 Å resolution X-ray crystal structure of a potent cryptophycin derivative bound to the αβ-tubulin heterodimer. The structure addresses conformational issues present in a previous 3.3 Å resolution cryo-electron microscopy structure of cryptophycin-52 bound to the maytansine site of β-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 studies. Interestingly, we discovered a second cryptophycin-binding site that involves the T5-loop of β-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 "βT5-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 β-tubulin binding sites. Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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