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| | ==High-resolution solution structure of the ASIC1a blocker PcTX1== | | ==High-resolution solution structure of the ASIC1a blocker PcTX1== |
| - | <StructureSection load='2kni' size='340' side='right' caption='[[2kni]], [[NMR_Ensembles_of_Models | 25 NMR models]]' scene=''> | + | <StructureSection load='2kni' size='340' side='right'caption='[[2kni]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2kni]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Psaca Psaca]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KNI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2KNI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2kni]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Psalmopoeus_cambridgei Psalmopoeus cambridgei]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KNI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2KNI FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1lmm|1lmm]]</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 25 models</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2kni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kni OCA], [http://pdbe.org/2kni PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2kni RCSB], [http://www.ebi.ac.uk/pdbsum/2kni PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2kni ProSAT]</span></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=2kni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kni OCA], [https://pdbe.org/2kni PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2kni RCSB], [https://www.ebi.ac.uk/pdbsum/2kni PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2kni ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TXP1_PSACA TXP1_PSACA]] Potently and selectively blocks the acid-sensing ion channel ASIC1a/ACCN2. The blockade is rapid and reversible. Psalmotoxin 1 loses its capacity to block ASIC1a/ACCN2 as soon as this subunit is associated with another member of the family (ASIC2a/ACCN1 or ASIC3/ACCN3). The toxin can distinguish between the two ASIC1/ACCN2 splice variants ASIC1a/ACCN2 and ASIC1b/ACCN2.<ref>PMID:10829030</ref> | + | [https://www.uniprot.org/uniprot/TXP1_PSACA TXP1_PSACA] Potently and selectively blocks the acid-sensing ion channel ASIC1a/ACCN2. The blockade is rapid and reversible. Psalmotoxin 1 loses its capacity to block ASIC1a/ACCN2 as soon as this subunit is associated with another member of the family (ASIC2a/ACCN1 or ASIC3/ACCN3). The toxin can distinguish between the two ASIC1/ACCN2 splice variants ASIC1a/ACCN2 and ASIC1b/ACCN2.<ref>PMID:10829030</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Psaca]] | + | [[Category: Large Structures]] |
| - | [[Category: King, G F]] | + | [[Category: Psalmopoeus cambridgei]] |
| - | [[Category: Mobli, M]] | + | [[Category: King GF]] |
| - | [[Category: Saez, N J]] | + | [[Category: Mobli M]] |
| - | [[Category: Acid sensing ion channel 1a inhibitor]] | + | [[Category: Saez NJ]] |
| - | [[Category: Asic1a inhibitor]]
| + | |
| - | [[Category: Cystine knot]]
| + | |
| - | [[Category: Disulfide bond]]
| + | |
| - | [[Category: Ionic channel inhibitor]]
| + | |
| - | [[Category: Knottin]]
| + | |
| - | [[Category: Neurotoxin]]
| + | |
| - | [[Category: Peptide toxin]]
| + | |
| - | [[Category: Pi-theraphotoxin-pc1a]]
| + | |
| - | [[Category: Psalmotoxin 1]]
| + | |
| - | [[Category: Secreted]]
| + | |
| - | [[Category: Spider toxin]]
| + | |
| - | [[Category: Toxin]]
| + | |
| Structural highlights
Function
TXP1_PSACA Potently and selectively blocks the acid-sensing ion channel ASIC1a/ACCN2. The blockade is rapid and reversible. Psalmotoxin 1 loses its capacity to block ASIC1a/ACCN2 as soon as this subunit is associated with another member of the family (ASIC2a/ACCN1 or ASIC3/ACCN3). The toxin can distinguish between the two ASIC1/ACCN2 splice variants ASIC1a/ACCN2 and ASIC1b/ACCN2.[1]
Publication Abstract from PubMed
Acid-sensing ion channel 1a (ASIC1a) is a primary acid sensor in the peripheral and central nervous system. It has been implicated as a novel therapeutic target for a broad range of pathophysiological conditions including pain, ischemic stroke, depression, and autoimmune diseases such as multiple sclerosis. The only known selective blocker of ASIC1a is pi-TRTX-Pc1a (PcTx1), a disulfide-rich 40-residue peptide isolated from spider venom. pi-TRTX-Pc1a is an effective analgesic in rodent models of acute pain and it provides neuroprotection in a mouse model of ischemic stroke. Thus, understanding the molecular basis of the pi-TRTX-Pc1a-ASIC1a interaction should facilitate development of therapeutically useful ASIC1a blockers. We therefore developed an efficient bacterial expression system to produce a panel of pi-TRTX-Pc1a mutants for probing structure-activity relationships as well as isotopically labeled toxin for determination of its solution structure and dynamics. We demonstrate that the toxin pharmacophore resides in a beta-hairpin loop that was revealed to be mobile over a wide range of time scales using molecular dynamics simulations in combination with NMR spin relaxation and relaxation dispersion measurements. The toxin-receptor interaction was modeled by in silico docking of the toxin structure onto a homology model of rat ASIC1a in a restraints-driven approach that was designed to take account of the dynamics of the toxin pharmacophore and the consequent remodeling of side-chain conformations upon receptor binding. The resulting model reveals new insights into the mechanism of action of pi-TRTX-Pc1a and provides an experimentally validated template for the rational design of therapeutically useful pi-TRTX-Pc1a mimetics.
A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a.,Saez NJ, Mobli M, Bieri M, Chassagnon IR, Malde AK, Gamsjaeger R, Mark AE, Gooley PR, Rash LD, King GF Mol Pharmacol. 2011 Nov;80(5):796-808. doi: 10.1124/mol.111.072207. Epub 2011 Aug, 8. PMID:21825095[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Escoubas P, De Weille JR, Lecoq A, Diochot S, Waldmann R, Champigny G, Moinier D, Menez A, Lazdunski M. Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J Biol Chem. 2000 Aug 18;275(33):25116-21. PMID:10829030 doi:http://dx.doi.org/10.1074/jbc.M003643200
- ↑ Saez NJ, Mobli M, Bieri M, Chassagnon IR, Malde AK, Gamsjaeger R, Mark AE, Gooley PR, Rash LD, King GF. A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a. Mol Pharmacol. 2011 Nov;80(5):796-808. doi: 10.1124/mol.111.072207. Epub 2011 Aug, 8. PMID:21825095 doi:http://dx.doi.org/10.1124/mol.111.072207
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