{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Scott DC"],"funding":["U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)","U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)","NIA NIH HHS","Howard Hughes Medical Institute","U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging","U.S. Department of Health &amp; Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute","Howard Hughes Medical Institute (HHMI)","Max-Planck-Gesellschaft (Max Planck Society)","U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute","NCI NIH HHS","U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)","U.S. Department of Health &amp; Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (National Cancer Institute Division of Cancer Epidemiology and Genetics)","Max-Planck-Gesellschaft","NIGMS NIH HHS","U.S. Department of Health &amp; Human Services | National Institutes of Health"],"pagination":["8829"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11470957"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(1)"],"pubmed_abstract":["PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-substrate selectivity beyond that established by POI binding to the ligand alone. Here, we extend the collection of ubiquitin ligases employable for cooperative ternary complex formation to include the C-degron E3 KLHDC2. Ligands were identified that engage the C-degron binding site in KLHDC2, subjected to structure-based improvement, and linked to JQ1 for BET-family neo-substrate recruitment. Consideration of the exit vector emanating from the ligand engaged in KLHDC2's U-shaped degron-binding pocket enabled generation of SJ46421, which drives formation of a remarkably cooperative, paralog-selective ternary complex with BRD3<sup>BD2</sup>. Meanwhile, screening pro-drug variants enabled surmounting cell permeability limitations imposed by acidic moieties resembling the KLHDC2-binding C-degron. Selectivity for BRD3 compared to other BET-family members is further manifested in ubiquitylation in vitro, and prodrug version SJ46420-mediated degradation in cells. Selectivity is also achieved for the ubiquitin ligase, overcoming E3 auto-inhibition to engage KLHDC2, but not the related KLHDC1, KLHDC3, or KLHDC10 E3s. In sum, our study establishes neo-substrate-specific targeted protein degradation via KLHDC2, and provides a framework for developing selective PROTAC protein degraders employing C-degron E3 ligases."],"journal":["Nature communications"],"pubmed_title":["Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2."],"pmcid":["PMC11470957"],"funding_grant_id":["R01 GM132129","P30 CA021765","5RO1CA247365","Schulman department","NIH P30CA021765","P30 GM133893","R01GM132129","R01 CA247365","R01 AG011085","Investigator","NIH R01AG11085"],"pubmed_authors":["Chai SC","Loudon VC","Yang L","Ochoada J","Elledge SJ","Ronnebaum J","Lee RE","Scott DC","King MT","Lee HW","Gee CT","Harper JW","Dharuman S","Lee C","Li Y","Tangallapally R","Jayasinghe T","Paulo JA","Schulman BA","Miller DJ","Griffith E","Chen T"],"additional_accession":[]},"is_claimable":false,"name":"Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2.","description":"PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-substrate selectivity beyond that established by POI binding to the ligand alone. Here, we extend the collection of ubiquitin ligases employable for cooperative ternary complex formation to include the C-degron E3 KLHDC2. Ligands were identified that engage the C-degron binding site in KLHDC2, subjected to structure-based improvement, and linked to JQ1 for BET-family neo-substrate recruitment. Consideration of the exit vector emanating from the ligand engaged in KLHDC2's U-shaped degron-binding pocket enabled generation of SJ46421, which drives formation of a remarkably cooperative, paralog-selective ternary complex with BRD3<sup>BD2</sup>. Meanwhile, screening pro-drug variants enabled surmounting cell permeability limitations imposed by acidic moieties resembling the KLHDC2-binding C-degron. Selectivity for BRD3 compared to other BET-family members is further manifested in ubiquitylation in vitro, and prodrug version SJ46420-mediated degradation in cells. Selectivity is also achieved for the ubiquitin ligase, overcoming E3 auto-inhibition to engage KLHDC2, but not the related KLHDC1, KLHDC3, or KLHDC10 E3s. In sum, our study establishes neo-substrate-specific targeted protein degradation via KLHDC2, and provides a framework for developing selective PROTAC protein degraders employing C-degron E3 ligases.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Oct","modification":"2026-06-30T03:09:23.235Z","creation":"2025-04-04T01:24:54.578Z"},"accession":"S-EPMC11470957","cross_references":{"pubmed":["39396041"],"doi":["10.1038/s41467-024-52966-3"]}}