PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101087697 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-4186 (Electronic) Linking ISSN: 09692126 NLM ISO Abbreviation: Structure Subsets: MEDLINE
    • Publication Information:
      Publication: 2000- : Cambridge, Mass. : Cell Press
      Original Publication: London : Current Biology, c1993-
    • Subject Terms:
      Proteolysis* ; Protein Binding* ; Ubiquitin-Protein Ligases*/metabolism ; Ubiquitin-Protein Ligases*/chemistry ; Pregnane X Receptor*/metabolism ; Pregnane X Receptor*/chemistry; Humans ; Ligands ; Binding Sites ; Crystallography, X-Ray ; Models, Molecular
    • Abstract:
      Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules containing a ligand for a protein of interest linked to an E3 ubiquitin ligase ligand that induce protein degradation through E3 recruitment to the target protein. Small changes in PROTAC linkers can have drastic consequences, including loss of degradation activity, but the structural mechanisms governing such changes are unclear. To study this phenomenon, we screened PROTACs of diverse targeting modalities and identified dTAG-13 as an activator of the xenobiotic-sensing pregnane X receptor (PXR), which promiscuously binds various ligands. Characterization of dTAG-13 analogs and precursors revealed interplay between the PXR-binding moiety, linker, and E3 ligand that altered PXR activity without inducing degradation. A crystal structure of PXR ligand binding domain bound to a precursor ligand showed ligand-induced binding pocket distortions and a linker-punctured tunnel to the protein exterior at a region incompatible with E3 complex formation, highlighting the effects of linker environment on PROTAC activity.
      Competing Interests: Declaration of interests The authors declare no competing interests.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
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    • Grant Information:
      P30 GM133893 United States GM NIGMS NIH HHS; R35 GM118041 United States GM NIGMS NIH HHS
    • Contributed Indexing:
      Keywords: PROTAC; cytochrome P450; drug design; metabolism; nuclear receptor; pregnane X receptor; targeted protein degradation
    • Accession Number:
      0 (Ligands)
      EC 2.3.2.27 (Ubiquitin-Protein Ligases)
      0 (Pregnane X Receptor)
    • Publication Date:
      Date Created: 20241010 Date Completed: 20241206 Latest Revision: 20250104
    • Publication Date:
      20250104
    • Accession Number:
      PMC11647748
    • Accession Number:
      10.1016/j.str.2024.09.016
    • Accession Number:
      39389062