De novo-designed transmembrane proteins bind and regulate a cytokine receptor.
Nat Chem Biol
; 20(6): 751-760, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38480980
ABSTRACT
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 11 stoichiometry. Thus, membrane protein TM regions can now be targeted in custom-designed topologies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ligação Proteica
/
Receptores da Eritropoetina
/
Proteínas de Membrana
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Chem Biol
Assunto da revista:
BIOLOGIA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos