This study explores the development of high-affinity ligands for GID4 – the substrate receptor for the human CTLH E3 ligase. The cover image depicts the structural plasticity of GID4, highlighting three discrete conformational states—closed, semi-open, and open—induced by specific ligand binding. Through structure-based drug design, it was identified how these ligand-dependent shifts remodel the binding pocket. Analyzing how ligand-GID4 complexes cluster can clarify the links between chemical structure and biological activity, aiding the development of new ligands tailored for targeted protein degradation. More details can be found in the Research Article by Michal J. Walczak and co-workers (DOI: 10.1002/cmdc.202500849).
Kotlarek et al. (Tue,) studied this question.