PRE-CONFERENCE WORKSHOP - Tuesday May 7, 2024

1:30 – 2:00 | Check-In & Coffee

2:00 – 5:00 | Deep-Dive Workshop

Spearheading Time-Resolved Cryo-EM to Integrate Structural Dynamics Studies into Ligase-Targeted Drug Discovery

Synopsis

Unlocking the therapeutic potential of ubiquitin ligase targeting drugs, in particular in the context of targeted protein degradation, involves a deep understanding of ligase drug and the ternary ligase-drug-target interactions. However traditional profiling of ternary complexes formation is confronted by many bottlenecks including challenges to sample preparation for structural studies due to heterogeneity and conformational flexibility as well as, crucially the contrast between static characterization. Advances in cryo-EM allow researchers to visualize dynamic changes and can be integrated with temporal information to enhance our understanding of protein conformational changes, substrate binding, and enzymatic mechanisms crucial for targeted protein degradation. By merging quantitative biochemistry and structural biology, timeresolved Cryo-EM could facilitate more rational design of ligands with optimized drug efficacy and selectivity.

This workshop will discuss:

  • What are the methods for observing ternary complex formation? And what are their value for enabling SAR?
  • What are the advantages and challenges of cryo-EM and single particle analysis?
  • In the context of E3 ligases relevant to TPD, how to characterize conformational dynamics?
  • What are the advanced approaches to observe ternary complex formation and ubiquitin transfer?
  • How is time-resolved cryo-EM spearheading drug discovery by merging quantitative biochemistry and structural biology?