9HYP

CRYSTAL STRUCTURE OF THE SMARCA2-VCB-COMPLEX WITH PROTAC P5

This is a non-PDB format compatible entry.

Summary for 9HYP

• Entry DOI: 10.2210/pdb9hyp/pdb
• Related: 9HYB
• Descriptor: Probable global transcription activator SNF2L2, Elongin-B, Elongin-C, ... (6 entities in total)
• Functional Keywords: bromodomain, complex, e3-ligase, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 56858.97

Authors

Roy, M.J. (deposition date: 2025-01-10, release date: 2025-10-22)

Primary citation

Ma, N.,Bhattacharya, S.,Muk, S.,Jandova, Z.,Schmalhorst, P.S.,Ghosh, S.,Le, K.,Diers, E.,Trainor, N.,Farnaby, W.,Roy, M.J.,Kofink, C.,Greb, P.,Weinstabl, H.,Ciulli, A.,Bader, G.,Sankar, K.,Bergner, A.,Vaidehi, N.
Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes.
Nat Commun, 16:8595-8595, 2025

PubMed 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.

PubMed: 41022846
DOI: 10.1038/s41467-025-63713-7

Experimental method

X-RAY DIFFRACTION (2.2 Å)