Targeted protein degradation via intramolecular bivalent glues

Oliver Hsia, Matthias Hinterndorfer, Angus D. Cowan, Kentaro Iso, Tasuku Ishida, Ramasubramanian Sundaramoorthy, Mark A. Nakasone, Hana Imrichova, Caroline Schätz, Andrea Rukavina, Koraljka Husnjak, Martin Wegner, Alejandro Correa-Sáez, Conner Craigon, Ryan Casement, Chiara Maniaci, Andrea Testa, Manuel Kaulich, Ivan Dikic, Georg E. Winter () and Alessio Ciulli ()
Additional contact information
Oliver Hsia: University of Dundee
Matthias Hinterndorfer: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Angus D. Cowan: University of Dundee
Kentaro Iso: University of Dundee
Tasuku Ishida: University of Dundee
Ramasubramanian Sundaramoorthy: University of Dundee
Mark A. Nakasone: University of Dundee
Hana Imrichova: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Caroline Schätz: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Andrea Rukavina: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Koraljka Husnjak: Goethe University Frankfurt
Martin Wegner: Goethe University Frankfurt
Alejandro Correa-Sáez: University of Dundee
Conner Craigon: University of Dundee
Ryan Casement: University of Dundee
Chiara Maniaci: University of Dundee
Andrea Testa: University of Dundee
Manuel Kaulich: Goethe University Frankfurt
Ivan Dikic: Goethe University Frankfurt
Georg E. Winter: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Alessio Ciulli: University of Dundee

Nature, 2024, vol. 627, issue 8002, 204-211

Abstract: Abstract Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target1–4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target–ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4–IBG1–DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.

Date: 2024
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DOI: 10.1038/s41586-024-07089-6

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