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. 2024 May 15:104:129728.
doi: 10.1016/j.bmcl.2024.129728. Epub 2024 Apr 4.

Antascomicin B stabilizes FKBP51-Akt1 complexes as a molecular glue

Sabine C Schäfer  1 , Andreas M Voll  1 , Andreas Bracher  2 , Steven V Ley  3 , Felix Hausch  4
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Free article

Antascomicin B stabilizes FKBP51-Akt1 complexes as a molecular glue

Sabine C Schäfer et al. Bioorg Med Chem Lett. .
Free article

Abstract

Antascomicin B is a natural product that similarly to the macrolides FK506 and Rapamycin binds to the FK506-binding protein 12 (FKBP12). FK506 and Rapamycin act as molecular glues by inducing ternary complexes between FKBPs and additional target proteins. Whether Antascomicin B can induce ternary complexes is unknown. Here we show that Antascomicin B binds tightly to larger human FKBP homologs. The cocrystal structure of FKBP51 in complex with Antascomicin B revealed that large parts of Antascomicin B are solvent-exposed and available to engage additional proteins. Cellular studies demonstrated that Antascomicin B enhances the interaction between human FKBP51 and human Akt. Our studies show that molecules with molecular glue-like properties are more prominent in nature than previously thought. We predict the existence of additional 'orphan' molecular glues that evolved to induce ternary protein complexes but where the relevant ternary complex partners are unknown.

Keywords: Akt1; Antascomicin; FKBP; FKBP51; Molecular glues; PKB-beta; Protein–protein stabilizers.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Felix Hausch reports financial support was provided by Technical University of Darmstadt. Felix Hausch reports a relationship with Federal Ministry of Education and Research Berlin Office that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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