BacPROTACs mediate targeted protein degradation in bacteria.
AAA proteases
antimicrobials
bacterial PROTACs
targeted protein degradation
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
23 06 2022
23 06 2022
Historique:
received:
25
11
2020
revised:
15
03
2022
accepted:
10
05
2022
pubmed:
7
6
2022
medline:
29
6
2022
entrez:
6
6
2022
Statut:
ppublish
Résumé
Hijacking the cellular protein degradation system offers unique opportunities for drug discovery, as exemplified by proteolysis-targeting chimeras. Despite their great promise for medical chemistry, so far, it has not been possible to reprogram the bacterial degradation machinery to interfere with microbial infections. Here, we develop small-molecule degraders, so-called BacPROTACs, that bind to the substrate receptor of the ClpC:ClpP protease, priming neo-substrates for degradation. In addition to their targeting function, BacPROTACs activate ClpC, transforming the resting unfoldase into its functional state. The induced higher-order oligomer was visualized by cryo-EM analysis, providing a structural snapshot of activated ClpC unfolding a protein substrate. Finally, drug susceptibility and degradation assays performed in mycobacteria demonstrate in vivo activity of BacPROTACs, allowing selective targeting of endogenous proteins via fusion to an established degron. In addition to guiding antibiotic discovery, the BacPROTAC technology presents a versatile research tool enabling the inducible degradation of bacterial proteins.
Identifiants
pubmed: 35662409
pii: S0092-8674(22)00593-1
doi: 10.1016/j.cell.2022.05.009
pmc: PMC9240326
pii:
doi:
Substances chimiques
Bacterial Proteins
0
Molecular Chaperones
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2338-2353.e18Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests F.E.M., S.K., J.L., A.M., M.K., and T.C. are named as inventors of a patent that is based on the presented findings. G.B., H.W., K.R., and V.M.S. were employees of Boehringer Ingelheim at the time of this work.
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