Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
26 Jun 2024
26 Jun 2024
Historique:
received:
29
01
2024
accepted:
18
06
2024
medline:
27
6
2024
pubmed:
27
6
2024
entrez:
26
6
2024
Statut:
epublish
Résumé
Targeted protein degradation (TPD) relies on small molecules to recruit proteins to E3 ligases to induce their ubiquitylation and degradation by the proteasome. Only a few of the approximately 600 human E3 ligases are currently amenable to this strategy. This limits the actionable target space and clinical opportunities and thus establishes the necessity to expand to additional ligases. Here we identify and characterize SP3N, a specific degrader of the prolyl isomerase FKBP12. SP3N features a minimal design, where a known FKBP12 ligand is appended with a flexible alkylamine tail that conveys degradation properties. We found that SP3N is a precursor and that the alkylamine is metabolized to an active aldehyde species that recruits the SCF
Identifiants
pubmed: 38926334
doi: 10.1038/s41467-024-49739-3
pii: 10.1038/s41467-024-49739-3
doi:
Substances chimiques
F-Box Proteins
0
FBXO22 protein, human
0
Tacrolimus Binding Protein 1A
EC 5.2.1.-
Ubiquitin-Protein Ligases
EC 2.3.2.27
Amines
0
Proteasome Endopeptidase Complex
EC 3.4.25.1
Ligands
0
Receptors, Cytoplasmic and Nuclear
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5409Subventions
Organisme : Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
ID : P7909
Organisme : Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
ID : P36746
Organisme : Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
ID : P5918723
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 851478
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 789016
Informations de copyright
© 2024. The Author(s).
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