5epm

Ceratotoxin variant in complex with specific antibody Fab fragment

spinqualitylabelsall models 5epm, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5epm is a 6 chain structure with sequence from Ceratogyrus marshalli and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: PCA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TX1_CERMR Publication Abstract from PubMed The prominent role of voltage-gated sodium channel 1.7 (Nav1.7) in nociception was revealed by remarkable human clinical and genetic evidence. Development of potent and subtypeselective inhibitors of this ion channel is crucial for obtaining therapeutically useful analgesic compounds. Microproteins isolated from animal venoms have been identified as promising therapeutic leads for ion channels, since they naturally evolved to be potent ion channel blockers. Here we report the engineering of highly potent and selective inhibitors of Nav1.7 channel based on tarantula Ceratotoxin-1 (CcoTx1). We utilized a combination of directed evolution, saturation mutagenesis, chemical modification, and rational drug design to obtain higher potency and selectivity to Nav1.7 channel. The resulting microproteins are highly potent (IC50 to Nav1.7 of 2.5 nM) and selective. We achieved 80-fold and 20-fold selectivity over the closely related Nav1.2 and Nav1.6 channels, respectively, and the IC50 on skeletal (Nav1.4) and cardiac (Nav1.5) sodium channels is above 3000nM. The lead molecules have the potential for future clinical development as novel therapeutics in the treatment of pain. Engineering Highly Potent and Selective Microproteins Against Nav1.7 Sodium Channel for Treatment of Pain.,Shcherbatko A, Rossi A, Foletti D, Zhu G, Bogin O, Galindo-Casas M, Rickert M, Hasa-Moreno A, Bartevitch V, Crameri A, Steiner AR, Henningsen R, Gill A, Pons J, Shelton DL, Rajpal A, Strop P J Biol Chem. 2016 Apr 22. pii: jbc.M116.725978. PMID:27129258 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Antibody 3D structures 3D structures of non-human antibody

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