Protein Degraders & Ternary Complexes: PROTAC® Degraders
Cryo-EM structure determination for PROTAC®-mediated ternary complexes.
Proteolysis-Targeting Chimeras (PROTACs®) use a bivalent design, combining a target-protein warhead and an E3 ligase ligand connected by a chemical linker, to bring two proteins that don't interact physiologically into close proximity and drive targeted degradation. Because these linkers are highly flexible, the resulting ternary complexes pose challenges for traditional X-ray crystallization.
Cryo-EM is ideally suited to capture these flexible complexes in their near-native solution states, providing the structural data needed to move from empirical screening to rational PROTAC® design.
TrueCourse Experience with PROTACs®
Protein Degraders & Ternary Complexes are among the target classes solved at TrueCourse, including both PROTAC® Degraders and Molecular Glues.
Related Publication
The study employed a comprehensive structural workflow to characterize the interactions between the degraders, the target protein PTPN2/N1, and the E3 ubiquitin ligase CRBN-DDB1. Crystal structure analysis revealed the recognition of PTPN2 by the degrader, and high-resolution cryo-EM structure determination demonstrated large conformational heterogeneity of the ternary complex induced by the degraders. Molecular dynamic simulations further revealed a large rigid body movement of PTPN2 and illustrated dynamic interactions between PTPN2 and CRBN, highlighting the plasticity and dynamic nature of degrader-induced protein-protein interactions.
What Cryo-EM Reveals
- Full spatial range of the E3 Ligase-PROTAC®-Target complex
- Multiple conformational states from a single experiment
- Structural basis of protein-protein interactions
- Ligand binding and linker geometry
X-ray Crystallography for PROTACs®
While cryo-EM is ideally suited to capture flexible ternary complexes, X-ray crystallography provides high-resolution 3D structures for targets where crystallization is achievable. For PROTAC® programs where binary complexes or individual binding partners can be crystallized, X-ray crystallography reveals binding modes and informs medicinal chemistry.
TrueCourse offers both cryo-EM and X-ray crystallography, ensuring the right technique is applied to your target. Whether your target crystallizes or not, our team delivers the high-resolution structural data that accelerates drug discovery.
