2kni

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[[Image:2kni.png|left|200px]]
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==High-resolution solution structure of the ASIC1a blocker PcTX1==
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<StructureSection load='2kni' size='340' side='right' caption='[[2kni]], [[NMR_Ensembles_of_Models | 25 NMR models]]' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2kni]] is a 1 chain structure with sequence from [http://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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2KNI FirstGlance]. <br>
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</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1lmm|1lmm]]</td></tr>
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<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://www.rcsb.org/pdb/explore.do?structureId=2kni RCSB], [http://www.ebi.ac.uk/pdbsum/2kni PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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{{STRUCTURE_2kni| PDB=2kni | SCENE= }}
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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<ref>PMID:21825095</ref>
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===High-resolution solution structure of the ASIC1a blocker PcTX1===
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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{{ABSTRACT_PUBMED_21825095}}
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== References ==
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<references/>
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==About this Structure==
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__TOC__
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[[2kni]] is a 1 chain structure with sequence from [http://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].
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</StructureSection>
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==Reference==
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<ref group="xtra">PMID:012824480</ref><references group="xtra"/>
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[[Category: Psalmopoeus cambridgei]]
[[Category: Psalmopoeus cambridgei]]
[[Category: King, G F.]]
[[Category: King, G F.]]

Revision as of 09:26, 5 November 2014

High-resolution solution structure of the ASIC1a blocker PcTX1

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