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Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules.
Hickey, Christopher M; Digianantonio, Katherine M; Zimmermann, Kurt; Harbin, Alicia; Quinn, Connor; Patel, Avani; Gareiss, Peter; Chapman, Amanda; Tiberi, Bernadette; Dobrodziej, Jennifer; Corradi, John; Cacace, Angela M; Langley, David R; Békés, Miklós.
Afiliación
  • Hickey CM; Arvinas, Inc, New Haven, CT, USA.
  • Digianantonio KM; Arvinas, Inc, New Haven, CT, USA.
  • Zimmermann K; Arvinas, Inc, New Haven, CT, USA.
  • Harbin A; Arvinas, Inc, New Haven, CT, USA.
  • Quinn C; Arvinas, Inc, New Haven, CT, USA.
  • Patel A; Arvinas, Inc, New Haven, CT, USA.
  • Gareiss P; Arvinas, Inc, New Haven, CT, USA.
  • Chapman A; Arvinas, Inc, New Haven, CT, USA.
  • Tiberi B; Arvinas, Inc, New Haven, CT, USA.
  • Dobrodziej J; Genetics, Genomics and Cancer Biology Graduate Program, Thomas Jefferson University, Philadelphia, PA, USA.
  • Corradi J; Arvinas, Inc, New Haven, CT, USA.
  • Cacace AM; Accent Therapeutics Inc, Lexington, MA, USA.
  • Langley DR; Arvinas, Inc, New Haven, CT, USA.
  • Békés M; Arvinas, Inc, New Haven, CT, USA.
Nat Struct Mol Biol ; 31(2): 311-322, 2024 Feb.
Article en En | MEDLINE | ID: mdl-38177675
ABSTRACT
Targeted protein degradation (TPD) by PROTAC (proteolysis-targeting chimera) and molecular glue small molecules is an emerging therapeutic strategy. To expand the roster of E3 ligases that can be utilized for TPD, we describe the discovery and biochemical characterization of small-molecule ligands targeting the E3 ligase KLHDC2. Furthermore, we functionalize these KLHDC2-targeting ligands into KLHDC2-based BET-family and AR PROTAC degraders and demonstrate KLHDC2-dependent target-protein degradation. Additionally, we offer insight into the assembly of the KLHDC2 E3 ligase complex. Using biochemical binding studies, X-ray crystallography and cryo-EM, we show that the KLHDC2 E3 ligase assembles into a dynamic tetramer held together via its own C terminus, and that this assembly can be modulated by substrate and ligand engagement.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ubiquitina-Proteína Ligasas Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ubiquitina-Proteína Ligasas Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos