4u90

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

spinqualitylabelsall models 4u90, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4u90 is a 3 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3F8, BU1 Related: 4u91, 4pd0, 4pd1, 4tk1, 4tk2, 4tk3, 4tk4 Gene: Gphn, Gph (Buffalo rat) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [GEPH_RAT] Microtubule-associated protein involved in membrane protein-cytoskeleton interactions. It is thought to anchor the inhibitory glycine receptor (GLYR) to subsynaptic microtubules (By similarity). Catalyzes two steps in the biosynthesis of the molybdenum cofactor. In the first step, molybdopterin is adenylated. Subsequently, molybdate is inserted into adenylated molybdopterin and AMP is released. [GBRA3_RAT] GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. Publication Abstract from PubMed 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. Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors.,Maric HM, Kasaragod VB, Haugaard-Kedstrom L, Hausrat TJ, Kneussel M, Schindelin H, Stromgaard K Angew Chem Int Ed Engl. 2014 Nov 20. doi: 10.1002/anie.201409043. PMID:25413248 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also GABA receptor Gephyrin

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