Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes

Ning Ma (), Supriyo Bhattacharya, Sanychen Muk, Zuzana Jandova, Philipp S. Schmalhorst, Soumadwip Ghosh, Keith Le, Emelyne Diers, Nicole Trainor, William Farnaby, Michael J. Roy, Christiane Kofink, Peter Greb, Harald Weinstabl, Alessio Ciulli, Gerd Bader, Kyra Sankar, Andreas Bergner () and Nagarajan Vaidehi ()
Additional contact information
Ning Ma: Beckman Research Institute of the City of Hope
Supriyo Bhattacharya: Beckman Research Institute of the City of Hope
Sanychen Muk: Beckman Research Institute of the City of Hope
Zuzana Jandova: Boehringer Ingelheim RCV GmbH & Co KG
Philipp S. Schmalhorst: Boehringer Ingelheim RCV GmbH & Co KG
Soumadwip Ghosh: Beckman Research Institute of the City of Hope
Keith Le: Beckman Research Institute of the City of Hope
Emelyne Diers: University of Dundee
Nicole Trainor: University of Dundee
William Farnaby: University of Dundee
Michael J. Roy: University of Dundee
Christiane Kofink: Boehringer Ingelheim RCV GmbH & Co KG
Peter Greb: Boehringer Ingelheim RCV GmbH & Co KG
Harald Weinstabl: Boehringer Ingelheim RCV GmbH & Co KG
Alessio Ciulli: University of Dundee
Gerd Bader: Boehringer Ingelheim RCV GmbH & Co KG
Kyra Sankar: Boehringer Ingelheim RCV GmbH & Co KG
Andreas Bergner: Boehringer Ingelheim RCV GmbH & Co KG
Nagarajan Vaidehi: Beckman Research Institute of the City of Hope

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63713-7

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