Rigidified Clicked Dimeric Ligands for Studying the Dynamics of the PDZ1‐2 Supramodule of PSD‐95 |
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| Authors: | Dr. Jonas N. N. Eildal Dr. Anders Bach Dr. Jakob Dogan Dr. Fei Ye Prof. Mingjie Zhang Dr. Per Jemth Prof. Kristian Strømgaard |
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| Affiliation: | 1. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark);2. Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, 75123 Uppsala (Sweden);3. Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (China) |
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| 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. |
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| Keywords: | dimeric ligands NMR spectroscopy PDZ domains protein– protein interactions PSD‐95 |
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