De novo-designed transmembrane proteins bind and regulate a cytokine receptor.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
13 Mar 2024
13 Mar 2024
Historique:
received:
14
02
2023
accepted:
25
01
2024
medline:
14
3
2024
pubmed:
14
3
2024
entrez:
14
3
2024
Statut:
aheadofprint
Résumé
Transmembrane (TM) domains as simple as a single span can perform complex biological functions using entirely lipid-embedded chemical features. Computational design has the potential to generate custom tool molecules directly targeting membrane proteins at their functional TM regions. Thus far, designed TM domain-targeting agents have been limited to mimicking the binding modes and motifs of natural TM interaction partners. Here, we demonstrate the design of de novo TM proteins targeting the erythropoietin receptor (EpoR) TM domain in a custom binding topology competitive with receptor homodimerization. The TM proteins expressed in mammalian cells complex with EpoR and inhibit erythropoietin-induced cell proliferation. In vitro, the synthetic TM domain complex outcompetes EpoR homodimerization. Structural characterization reveals that the complex involves the intended amino acids and agrees with our designed molecular model of antiparallel TM helices at 1:1 stoichiometry. Thus, membrane protein TM regions can now be targeted in custom-designed topologies.
Identifiants
pubmed: 38480980
doi: 10.1038/s41589-024-01562-z
pii: 10.1038/s41589-024-01562-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : GM68933
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : CA037157
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R35-122603
Informations de copyright
© 2024. The Author(s).
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