Heterobifunctional degraders rely on the formation of productive ternary complexes to activate cellular
degradative machinery, causing the proteolysis of a protein of interest (POI).1 Typically, the POI is tethered to an E3 ubiquitin ligase protein, which, downstream, leads to the degradation of the POI via the ubiquitin degradation pathway (Figure 1). These ternary complexes are dynamic in nature, and various differing protein–protein conformations can lead to a degradation event. This poses a unique challenge for structure-based drug design, as there are multiple correct solutions for the protein–protein conformations.
Whilst crystallographic structures of these complexes were once rare, their availability has steadily increased over the years. Scientists have collated a database of publicly available heterobifunctional degrader-containing ternary complex crystal structures.2 Through careful analysis of these structures, the biological assemblies of these complexes were investigated, with the aim of discovering whether these assemblies provide information on the viability of ternary complex conformations induced by heterobifunctional degrader molecules.
Protein crystallography produces solid-state assemblies of molecules, which can come in different forms. One of the challenges of computational drug design is deducing whether these assemblies are biologically relevant. In particular, crystal packing forces can distort or otherwise alter the configuration of the ternary complex. Examination of the crystallographic symmetry mates of heterobifunctional molecule-containing ternary complexes can help determine whether this is the case. All modelling and analysis were performed using Flare™.3
