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TitleContinuous evolution of compact protein degradation tags regulated by selective molecular glues.
Journal, issue, pagesScience, Vol. 383, Issue 6688, Page eadk4422, Year 2024
Publish dateMar 15, 2024
AuthorsJaron A M Mercer / Stephan J DeCarlo / Shourya S Roy Burman / Vedagopuram Sreekanth / Andrew T Nelson / Moritz Hunkeler / Peter J Chen / Katherine A Donovan / Praveen Kokkonda / Praveen K Tiwari / Veronika M Shoba / Arghya Deb / Amit Choudhary / Eric S Fischer / David R Liu /
PubMed AbstractConditional 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 ...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.
External linksScience / PubMed:38484051 / PubMed Central
MethodsEM (single particle)
Resolution2.41 - 3.37 Å
Structure data

41423

8tnp

EMDB-41423, PDB-8tnp:
Cryo-EM structure of DDB1dB:CRBN:Pomalidomide:SD40
Method: EM (single particle) / Resolution: 3.3 Å

41424

8tnq

EMDB-41424, PDB-8tnq:
Cryo-EM structure of DDB1dB:CRBN:PT-179:SD40, conformation 1
Method: EM (single particle) / Resolution: 2.41 Å

41425

8tnr

EMDB-41425, PDB-8tnr:
Cryo-EM structure of DDB1dB:CRBN:PT-179:SD40, conformation 2
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-41777: Map from local refinement (focused on CRBN) of DDB1dB:CRBN:Pomalidomide:SD40
Method: EM (single particle) / Resolution: 3.37 Å

EMDB-41778: Map from local refinement (focused on CRBN) of DDB1dB:CRBN:PT-179:SD40, conformation 1
Method: EM (single particle) / Resolution: 2.55 Å

EMDB-41779: Map from local refinement (focused on CRBN) of DDB1dB:CRBN:PT-179:SD40, conformation 2
Method: EM (single particle) / Resolution: 2.72 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-Y70:
S-Pomalidomide


ChemComp, No image

ChemComp-MIQ:
Unknown entry

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsTRANSFERASE / ubiquitin / CRBN / directed evolution / Zinc finger / IMiD / Molecular Glue

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