EMD-41779

Single-particle
2.72 Å
EMD-41779 Deposition: 29/08/2023
Map released: 13/03/2024
Last modified: 03/04/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-41779

Map from local refinement (focused on CRBN) of DDB1dB:CRBN:PT-179:SD40, conformation 2

EMD-41779

Single-particle
2.72 Å
EMD-41779 Deposition: 29/08/2023
Map released: 13/03/2024
Last modified: 03/04/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Ternary Complex of DDB1dB:CRBN:PT-179 with SD40

Deposition Authors: Roy Burman SS , Hunkeler M , Fischer ES
Continuous evolution of compact protein degradation tags regulated by selective molecular glues.
PUBMED: 38484051
DOI: doi:10.1126/science.adk4422
ISSN: 1095-9203
ASTM: SCIEAS
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.