EMD-41779
Map from local refinement (focused on CRBN) of DDB1dB:CRBN:PT-179:SD40, conformation 2
EMD-41779
Single-particle2.72 Å
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Map released: 13/03/2024
Last modified: 03/04/2024
Sample Organism:
Homo sapiens
Sample: Ternary Complex of DDB1dB:CRBN:PT-179 with SD40
Deposition Authors: Roy Burman SS
,
Hunkeler M
,
Fischer ES
Sample: Ternary Complex of DDB1dB:CRBN:PT-179 with SD40
Deposition Authors: Roy Burman SS
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Continuous evolution of compact protein degradation tags regulated by selective molecular glues.
Mercer JAM
,
DeCarlo SJ
,
Roy Burman SS
,
Sreekanth V
,
Nelson AT,
Hunkeler M
,
Chen PJ
,
Donovan KA
,
Kokkonda P,
Tiwari PK
,
Shoba VM
,
Deb A,
Choudhary A
,
Fischer ES
,
Liu DR
(2024) Science , 383 , eadk4422 - eadk4422
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(2024) Science , 383 , eadk4422 - eadk4422
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.
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.