A rational blueprint for the design of chemically-controlled protein switches.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 10 2021
01 10 2021
Historique:
received:
23
01
2021
accepted:
24
08
2021
entrez:
2
10
2021
pubmed:
3
10
2021
medline:
25
2
2023
Statut:
epublish
Résumé
Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. However, the repertoire of small-molecule protein switches is insufficient for many applications, including those in the translational spaces, where properties such as safety, immunogenicity, drug half-life, and drug side-effects are critical. Here, we present a computational protein design strategy to repurpose drug-inhibited protein-protein interactions as OFF- and ON-switches. The designed binders and drug-receptors form chemically-disruptable heterodimers (CDH) which dissociate in the presence of small molecules. To design ON-switches, we converted the CDHs into a multi-domain architecture which we refer to as activation by inhibitor release switches (AIR) that incorporate a rationally designed drug-insensitive receptor protein. CDHs and AIRs showed excellent performance as drug responsive switches to control combinations of synthetic circuits in mammalian cells. This approach effectively expands the chemical space and logic responses in living cells and provides a blueprint to develop new ON- and OFF-switches.
Identifiants
pubmed: 34599176
doi: 10.1038/s41467-021-25735-9
pii: 10.1038/s41467-021-25735-9
pmc: PMC8486872
doi:
Substances chimiques
Receptors, Drug
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5754Informations de copyright
© 2021. The Author(s).
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