Continuous evolution of compact protein degradation tags regulated by selective molecular glues
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 molecu...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2024-03, Vol.383 (6688), p.eadk4422-eadk4422 |
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| creator | Mercer, Jaron A M DeCarlo, Stephan J Roy Burman, Shourya S Sreekanth, Vedagopuram Nelson, Andrew T Hunkeler, Moritz Chen, Peter J Donovan, Katherine A Kokkonda, Praveen Tiwari, Praveen K Shoba, Veronika M Deb, Arghya Choudhary, Amit Fischer, Eric S Liu, David R |
| description | 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. |
| doi_str_mv | 10.1126/science.adk4422 |
| format | Article |
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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.</description><identifier>ISSN: 0036-8075</identifier><identifier>ISSN: 1095-9203</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.adk4422</identifier><identifier>PMID: 38484051</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Amino acid substitution ; Amino acids ; Binding ; Biodegradation ; Biotechnology ; C-Terminus ; Coding ; Complex formation ; Degradation ; Dilution ; Drugs ; Editing ; Electron microscopy ; Evolution ; Genes ; Glues ; Immunomodulation ; Mammalian cells ; Mammals ; Modulators ; Narcotics ; Phages ; Proteasomes ; Protein folding ; Proteins ; Tags ; Target detection ; Thalidomide ; Ubiquitin-protein ligase ; Zinc ; Zinc finger proteins</subject><ispartof>Science (American Association for the Advancement of Science), 2024-03, Vol.383 (6688), p.eadk4422-eadk4422</ispartof><rights>Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-2f88c5fe131151bc06ad0c5ae2363b8bc02791a2ea8b2379fc54472a03bde35d3</citedby><cites>FETCH-LOGICAL-c422t-2f88c5fe131151bc06ad0c5ae2363b8bc02791a2ea8b2379fc54472a03bde35d3</cites><orcidid>0000-0002-9943-7557 ; 0000-0001-7337-6306 ; 0000-0001-8054-2317 ; 0000-0001-9274-9104 ; 0000-0002-7065-2675 ; 0000-0002-8147-6312 ; 0000-0002-8437-0150 ; 0000-0002-8539-5106 ; 0000-0002-1094-7180 ; 0000-0003-0402-7414 ; 0000-0001-7078-614X ; 0000-0003-0246-1188</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,2871,2872,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38484051$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mercer, Jaron A M</creatorcontrib><creatorcontrib>DeCarlo, Stephan J</creatorcontrib><creatorcontrib>Roy Burman, Shourya S</creatorcontrib><creatorcontrib>Sreekanth, Vedagopuram</creatorcontrib><creatorcontrib>Nelson, Andrew T</creatorcontrib><creatorcontrib>Hunkeler, Moritz</creatorcontrib><creatorcontrib>Chen, Peter J</creatorcontrib><creatorcontrib>Donovan, Katherine A</creatorcontrib><creatorcontrib>Kokkonda, Praveen</creatorcontrib><creatorcontrib>Tiwari, Praveen K</creatorcontrib><creatorcontrib>Shoba, Veronika M</creatorcontrib><creatorcontrib>Deb, Arghya</creatorcontrib><creatorcontrib>Choudhary, Amit</creatorcontrib><creatorcontrib>Fischer, Eric S</creatorcontrib><creatorcontrib>Liu, David R</creatorcontrib><title>Continuous evolution of compact protein degradation tags regulated by selective molecular glues</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>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.</description><subject>Amino acid substitution</subject><subject>Amino acids</subject><subject>Binding</subject><subject>Biodegradation</subject><subject>Biotechnology</subject><subject>C-Terminus</subject><subject>Coding</subject><subject>Complex formation</subject><subject>Degradation</subject><subject>Dilution</subject><subject>Drugs</subject><subject>Editing</subject><subject>Electron microscopy</subject><subject>Evolution</subject><subject>Genes</subject><subject>Glues</subject><subject>Immunomodulation</subject><subject>Mammalian cells</subject><subject>Mammals</subject><subject>Modulators</subject><subject>Narcotics</subject><subject>Phages</subject><subject>Proteasomes</subject><subject>Protein folding</subject><subject>Proteins</subject><subject>Tags</subject><subject>Target 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| ispartof | Science (American Association for the Advancement of Science), 2024-03, Vol.383 (6688), p.eadk4422-eadk4422 |
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| source | American Association for the Advancement of Science |
| subjects | Amino acid substitution Amino acids Binding Biodegradation Biotechnology C-Terminus Coding Complex formation Degradation Dilution Drugs Editing Electron microscopy Evolution Genes Glues Immunomodulation Mammalian cells Mammals Modulators Narcotics Phages Proteasomes Protein folding Proteins Tags Target detection Thalidomide Ubiquitin-protein ligase Zinc Zinc finger proteins |
| title | Continuous evolution of compact protein degradation tags regulated by selective molecular glues |
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