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Antascomicin B stabilizes FKBP51-Akt1 complexes as a molecular glue.

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Antascomicin B, a natural product, acts as a molecular glue by binding FKBP51 and enhancing its interaction with Akt. This discovery suggests more natural

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • FK506 and Rapamycin are macrolides that bind FKBP12 and function as molecular glues.
  • Molecular glues induce ternary complexes between FKBP proteins and other target proteins.
  • The molecular glue potential of Antascomicin B, a natural product, is currently unknown.

Purpose of the Study:

  • To investigate the interaction of Antascomicin B with FKBP proteins.
  • To determine if Antascomicin B can induce ternary complexes.
  • To explore the potential of Antascomicin B as a molecular glue.

Main Methods:

  • Cocrystallography of FKBP51 with Antascomicin B.
  • Cellular studies to assess protein-protein interactions.

Main Results:

  • Antascomicin B binds to larger human FKBP homologs, including FKBP51.
  • Cocrystal structure reveals solvent-exposed regions of Antascomicin B available for protein engagement.
  • Antascomicin B enhances the interaction between FKBP51 and Akt in cellular studies.

Conclusions:

  • Antascomicin B exhibits molecular glue-like properties.
  • Natural products with molecular glue capabilities may be more widespread than previously recognized.
  • The existence of additional 'orphan' molecular glues is predicted.