Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes
Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a promising strategy to eliminate previously undruggable proteins. PROTACs are bifunctional molecules that link a target protein with an E3 ubiquitin ligase, enabling the formation of a ternary complex that promotes ubiquitination and subsequent proteasomal degradation. Although many ternary complex structures are available, understanding how structural features relate to PROTAC function remains challenging due to the dynamic nature of these complexes. Here we show that the interface between the target protein SMARCA2 and the E3 ligase VHL is conformationally flexible and stabilized by interactions involving disordered loops. Using molecular dynamics simulations and X-ray crystallography of SMARCA2-VHL complexes bound to five different PROTACs, we find that interfacial residues often adopt energetically suboptimal, or 'frustrated,' configurations. We further show that the degree of frustration correlates with experimentally measured cooperativity for a set of 11 PROTACs. These findings suggest that quantifying interface frustration provides a rational, structure-based approach to guiding PROTAC design.
Authors
- Andreas Bergner (ORCID: https://orcid.org/0000-0002-5843-4325)
- Michael J. Roy (ORCID: https://orcid.org/0000-0003-0198-9108)
- Christiane Kofink
- K. Udaya Sankar
- Peter Greb (ORCID: https://orcid.org/0000-0002-6757-4370)
- Emelyne Diers (ORCID: https://orcid.org/0000-0001-5951-7918)
- William Farnaby (ORCID: https://orcid.org/0000-0001-8610-932X)
- Zuzana Jandová (ORCID: https://orcid.org/0000-0002-4890-344X)
- Alessio Ciulli (ORCID: https://orcid.org/0000-0002-8654-1670)
- Keith Le
- Harald Weinstabl (ORCID: https://orcid.org/0000-0003-1308-2730)
- Gerd Bader (ORCID: https://orcid.org/0000-0002-8410-3415)
- Nagarajan Vaidehi (ORCID: https://orcid.org/0000-0001-8100-8132)
- Sanychen Muk (ORCID: https://orcid.org/0000-0002-3490-8143)
- Nicole Trainor (ORCID: https://orcid.org/0000-0002-3758-9969)
- Soumadwip Ghosh (ORCID: https://orcid.org/0000-0002-9279-7066)
- Philipp S. Schmalhorst (ORCID: https://orcid.org/0000-0002-5795-0133)
- Ning Ma (ORCID: https://orcid.org/0000-0003-4653-7797)
- S. Bhattacharya (ORCID: https://orcid.org/0000-0003-0483-2149)
Institutions
- City Of Hope National Medical Center (US)
- University of Dundee (GB)
- Walter and Eliza Hall Institute of Medical Research (AU)
- City of Hope (US)
- AstraZeneca (Netherlands) (NL)
- Boehringer Ingelheim (Austria) (AT)
- AstraZeneca (Sweden) (SE)
- Beckman Research Institute
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s41467-025-63713-7
- Citations
- 5
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Wellcome Trust