8TNQ
Cryo-EM structure of DDB1dB:CRBN:PT-179:SD40, conformation 1
Summary for 8TNQ
| Entry DOI | 10.2210/pdb8tnq/pdb |
| EMDB information | 41423 41424 41425 |
| Descriptor | DNA damage-binding protein 1, Protein cereblon, Maltose/maltodextrin-binding periplasmic protein,SD40, ... (5 entities in total) |
| Functional Keywords | ubiquitin, crbn, directed evolution, zinc finger, imid, molecular glue, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 202118.70 |
| Authors | Roy Burman, S.S.,Hunkeler, M.,Fischer, E.S. (deposition date: 2023-08-02, release date: 2024-03-13, Last modification date: 2024-04-03) |
| Primary citation | Mercer, J.A.M.,DeCarlo, S.J.,Roy Burman, S.S.,Sreekanth, V.,Nelson, A.T.,Hunkeler, M.,Chen, P.J.,Donovan, K.A.,Kokkonda, P.,Tiwari, P.K.,Shoba, V.M.,Deb, A.,Choudhary, A.,Fischer, E.S.,Liu, D.R. Continuous evolution of compact protein degradation tags regulated by selective molecular glues. Science, 383:eadk4422-eadk4422, 2024 Cited by PubMed 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. PubMed: 38484051DOI: 10.1126/science.adk4422 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.41 Å) |
Structure validation
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