Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors
| Autor: | Hermann Schindelin, Torben J. Hausrat, Linda M. Haugaard-Kedström, Vikram Babu Kasaragod, Hans Michael Maric, Matthias Kneussel, Kristian Strømgaard |
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| Rok vydání: | 2014 |
| Předmět: |
Scaffold protein
Gephyrin biology Chemistry Molecular Sequence Data Membrane Proteins General Chemistry General Medicine Inhibitory neurotransmitter Catalysis Receptors Neurotransmitter Structural biology Biochemistry Struktur aktivitats beziehungen biology.protein Biophysics Structure–activity relationship Amino Acid Sequence Carrier Proteins Receptor Dimerization |
| Zdroj: | The Lens |
| ISSN: | 0044-8249 |
| DOI: | 10.1002/ange.201409043 |
| Popis: | Gephyrin is the central scaffolding protein for inhibitory neurotransmitter receptors in the brain. Here we describe the development of dimeric peptides that inhibit the interaction between gephyrin and these receptors, a process which is fundamental to numerous synaptic functions and diseases of the brain. We first identified receptor-derived minimal gephyrin-binding peptides that displayed exclusive binding towards native gephyrin from brain lysates. We then designed and synthesized a series of dimeric ligands, which led to a remarkable 1220-fold enhancement of the gephyrin affinity (KD=6.8 nM). In X-ray crystal structures we visualized the simultaneous dimer-to-dimer binding in atomic detail, revealing compound-specific binding modes. Thus, we defined the molecular basis of the affinity-enhancing effect of multivalent gephyrin inhibitors and provide conceptually novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin-receptor interplay. |
| Databáze: | OpenAIRE |
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