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| | <StructureSection load='5epm' size='340' side='right'caption='[[5epm]], [[Resolution|resolution]] 1.75Å' scene=''> | | <StructureSection load='5epm' size='340' side='right'caption='[[5epm]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5epm]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EPM OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5EPM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5epm]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Ceratogyrus_marshalli Ceratogyrus marshalli] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EPM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EPM FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5epm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5epm OCA], [http://pdbe.org/5epm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5epm RCSB], [http://www.ebi.ac.uk/pdbsum/5epm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5epm ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5epm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5epm OCA], [https://pdbe.org/5epm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5epm RCSB], [https://www.ebi.ac.uk/pdbsum/5epm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5epm ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TX1_CERMR TX1_CERMR] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| | *[[Antibody 3D structures|Antibody 3D structures]] | | *[[Antibody 3D structures|Antibody 3D structures]] |
| | + | *[[3D structures of non-human antibody|3D structures of non-human antibody]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Ceratogyrus marshalli]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Rossi, A]] | + | [[Category: Rossi A]] |
| - | [[Category: Shcherbatko, A]] | + | [[Category: Shcherbatko A]] |
| - | [[Category: Strop, P]] | + | [[Category: Strop P]] |
| - | [[Category: Ceratotoxin]]
| + | |
| - | [[Category: Nav1 7 ion chanel]]
| + | |
| - | [[Category: Random mutagenesis]]
| + | |
| - | [[Category: Toxin-immune system complex]]
| + | |
| Structural highlights
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. Engineering Highly Potent and Selective Microproteins Against Nav1.7 Sodium Channel for Treatment of Pain. J Biol Chem. 2016 Apr 22. pii: jbc.M116.725978. PMID:27129258 doi:http://dx.doi.org/10.1074/jbc.M116.725978
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