Continuous Evolution of Compact Protein Degradation Tags Regulated by Selective Molecular Glues

Overview

Journal Science

Specialty Science

Date 2024 Mar 14

PMID 38484051

Authors

Jaron 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

Affiliations

Soon will be listed here.

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.

Citing Articles

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