Continuous evolution of compact protein degradation tags regulated by selective molecular glues.
Science
; 383(6688): eadk4422, 2024 Mar 15.
Article
en En
| MEDLINE
| ID: mdl-38484051
ABSTRACT
Conditional protein degradation tags (degrons) are usually >100 amino acids long or are triggered by small molecules with substantial off-target effects, thwarting their use as specific modulators of endogenous protein levels. We developed a phage-assisted continuous evolution platform for molecular glue complexes (MG-PACE) and evolved a 36-amino acid zinc finger (ZF) degron (SD40) that binds the ubiquitin ligase substrate receptor cereblon in complex with PT-179, an orthogonal thalidomide derivative. Endogenous proteins tagged in-frame with SD40 using prime editing are degraded by otherwise inert PT-179. Cryo-electron microscopy structures of SD40 in complex with ligand-bound cereblon revealed mechanistic insights into the molecular basis of SD40's activity and specificity. Our efforts establish a system for continuous evolution of molecular glue complexes and provide ZF tags that overcome shortcomings associated with existing degrons.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Dedos de Zinc
/
Evolución Molecular Dirigida
/
Ubiquitina-Proteína Ligasas
/
Proteolisis
/
Degrones
Idioma:
En
Revista:
Science
Año:
2024
Tipo del documento:
Article