4U90

GephE in complex with PEG crosslinked GABA receptor alpha3 subunit derived dimeric peptide

Summary for 4U90

• Entry DOI: 10.2210/pdb4u90/pdb
• Related: 4PD0 4PD1 4TK1 4TK2 4TK3 4TK4 4U91
• Descriptor: Gephyrin, Gamma-aminobutyric acid receptor subunit alpha-3, 1,4-BUTANEDIOL, ... (5 entities in total)
• Functional Keywords: inhibitory synapse, scaffolding protein, gaba type a receptor, transferase, transfer protein - structural protein complex, transfer protein / structural protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cell junction, synapse : Q03555; Cell junction, synapse, postsynaptic cell membrane; Multi-pass membrane protein: P20236
• Total number of polymer chains: 3
• Total formula weight: 48279.34

Authors

Kasaragod, V.B.,Maric, H.M.,Schindelin, H. (deposition date: 2014-08-05, release date: 2014-12-10, Last modification date: 2023-12-20)

Primary citation

Maric, H.M.,Kasaragod, V.B.,Haugaard-Kedstrom, L.,Hausrat, T.J.,Kneussel, M.,Schindelin, H.,Strmgaard, K.
Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors.
Angew.Chem.Int.Ed.Engl., 54:490-494, 2015

PubMed Abstract: 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.

PubMed: 25413248
DOI: 10.1002/anie.201409043

Experimental method

X-RAY DIFFRACTION (2 Å)