2. Academic Validation
  3. Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2

Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2

  • Nat Commun. 2024 Oct 12;15(1):8829. doi: 10.1038/s41467-024-52966-3.
Daniel C Scott # 1,  Suresh Dharuman # 2,  Elizabeth Griffith 2,  Sergio C Chai 2,  Jarrid Ronnebaum 2,  Moeko T King 1,  Rajendra Tangallapally 2,  Chan Lee 3,  Clifford T Gee 2,  Lei Yang 2,  Yong Li 2,  Victoria C Loudon 2,  Ha Won Lee 2,  Jason Ochoada 2,  Darcie J Miller 1,  Thilina Jayasinghe 2,  Joao A Paulo 3,  Stephen J Elledge 4,  J Wade Harper 3,  Taosheng Chen 2,  Richard E Lee 5,  Brenda A Schulman 6 7
Affiliations

Affiliations

  • 1 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • 2 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 4 Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA. Richard.Lee@Stjude.org.
  • 6 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. schulman@biochem.mpg.de.
  • 7 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany. schulman@biochem.mpg.de.
  • # Contributed equally.
PMID: 39396041 DOI: 10.1038/s41467-024-52966-3
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 BRD3BD2. 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.

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