Movie of the molecular dynamics simulation of the opening and closing of the Cullin-RING protein complex

Heterobifunctional degraders, which consist of two separate protein binding moieties (the warhead and the E3-ligand) joined by a linker, are a class of molecules that "induce proximity" between a target protein of interest (POI) and a E3 ubiquitin ligase. This induced proximity can lead to ubiquitination of the POI and its subsequent proteosomal degradation through a complex machinery of proteins. TPD present a novel approach to drug protein targets, since a single degrader molecule can induce catalytic degradation of the POI and potentially offer an avenue to eliminate targets traditionally labeled as undruggable by classical therapeutic strategies. Here we probe the conformational landscape of the full CRL macromolecular assembly and present a MP4 trajectory movie showing the molecular dynamics simulation of the large-scale conformational change during the opening and closing of the Cullin-RING protein complex.