title: Rigidified clicked dimeric ligands for studying the dynamics of the PDZ1-2 supramodule of PSD-95.
abstract: 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.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark); Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, 75123 Uppsala (Sweden).
authors.forename: Jonas N N
authors.initials: JN
authors.lastname: Eildal
authors.forename: Anders
authors.initials: A
authors.lastname: Bach
authors.forename: Jakob
authors.initials: J
authors.lastname: Dogan
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.forename: Per
authors.initials: P
authors.lastname: Jemth
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D001665:Binding Sites; D019281:Dimerization; D000076122:Disks Large Homolog 4 Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D007700:Kinetics; D008024:Ligands; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry*
chemical_list: C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D054852:Small Molecule Libraries; D014230:Triazoles
keywords: NMR spectroscopy; PDZ domains; PSD-95; dimeric ligands; protein-protein interactions