Eildal, Jonas N N4; Bach, Anders5; Dogan, Jakob3; Ye, Fei3; Zhang, Mingjie3; Jemth, Per3; Strømgaard, Kristian5
1 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet2 Drug Research Academy M, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet3 unknown4 Drug Research Academy M, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet5 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet
PSD-95 is a scaffolding protein of the MAGUK protein family, and engages in several vital protein-protein interactions in the brain with its PDZ domains. It has been suggested that PSD-95 is composed of two supramodules, one of which is the PDZ1-2 tandem domain. Here we have developed rigidified high-affinity dimeric ligands that target the PDZ1-2 supramodule, and established the biophysical parameters of the dynamic PDZ1-2/ligand interactions. By employing ITC, protein NMR, and stopped-flow kinetics this study provides a detailed insight into the overall conformational energetics of the interaction between dimeric ligands and tandem PDZ domains. Our findings expand our understanding of the dynamics of PSD-95 with potential relevance to its biological role in interacting with multivalent receptor complexes and development of novel drugs.