Together, these findings indicate that PDZ1's conformational diversity represents an inherent biophysical property rather than a crystallographic artifact, suggest a functional division of labor in which PDZ1's structural plasticity enables broad ligand recognition via conformational selection while PDZ2's rigid architecture stabilizes the tandem domain arrangement, and provide an atomic-level framework for developing domain-selective therapeutics targeting syntenin-1 in cancer, viral infection, and neurodevelopmental disorders. Here, SDCBP is linked to neurodevelopmental disorder.