Protein Degraders & Ternary Complexes: Molecular Glues
Cryo-EM structure determination for molecular glue-mediated ternary complexes
Molecular glues are small molecules that function by remodeling a protein's surface to create novel protein-protein interactions, driving induced proximity between a target protein and an E3 ligase. Because these induced interfaces are flexible and difficult to crystallize, cryo-EM is ideally suited to capture the subtle conformational shifts that occur upon binding.
TrueCourse has proven experience with Protein Degraders & Ternary Complexes, including both PROTAC® Degraders and Molecular Glues, listed among our target classes solved
Why Cryo-EM for Molecular Glues
Traditional structural methods often struggle to capture the subtle conformational changes at these three-way interfaces. Cryo-EM can resolve:
- The three-way junction between ligase, glue, and target protein
- Surface topography changes induced by small molecule binding
- Near-atomic resolution details of the induced interface
What Cryo-EM Reveals
- One single cryo-EM experiment can often capture multiple conformational states and dynamic movements
- Provides insights into gating mechanisms, allosteric regulation, and interactions with ligands or modulators
- Recent technological advances have led to near-atomic resolution, allowing for detailed ligand interactions
- Identification and characterization of different functional states and subpopulations within the same sample
Drug Discovery Applications
Structural knowledge of ion channels in complex with pharmacological agents, toxins, or ligands can provide valuable insights into drug binding sites, mechanisms of action, and structure-activity relationships. These structures may aid in rational drug design and the development of novel therapeutics targeting ion channels in various diseases.
