2mpq: Difference between revisions
m Protected "2mpq" [edit=sysop:move=sysop] |
No edit summary |
||
| (8 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Solution structure of the sodium channel toxin Hd1a== | ||
<StructureSection load='2mpq' size='340' side='right'caption='[[2mpq]]' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2mpq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Haplopelma Haplopelma]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MPQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MPQ FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</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=2mpq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mpq OCA], [https://pdbe.org/2mpq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mpq RCSB], [https://www.ebi.ac.uk/pdbsum/2mpq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mpq ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
BACKGROUND AND PURPOSE: Chronic pain is a serious worldwide health issue, with current analgesics having limited efficacy and dose-limiting side effects. Humans with loss-of-function mutations in the voltage-gated sodium channel NaV 1.7 (hNaV 1.7) are indifferent to pain, making hNaV 1.7 a promising target for analgesic development. Since spider venoms are replete with NaV channel modulators, we examined their potential as a source of hNaV 1.7 inhibitors. EXPERIMENTAL APPROACH: We developed a high-throughput fluorescent-based assay to screen spider venoms against hNaV 1.7 and isolate 'hit' peptides. To examine the binding site of these peptides, we constructed a panel of chimeric channels in which the S3b-S4 paddle motif from each voltage sensor domain of hNaV 1.7 was transplanted into the homotetrameric KV 2.1 channel. KEY RESULTS: We screened 205 spider venoms and found that 40% contain at least one inhibitor of hNaV 1.7. By deconvoluting 'hit' venoms, we discovered seven novel members of the NaSpTx family 1. One of these peptides, Hd1a (peptide mu-TRTX-Hd1a from venom of the spider Haplopelma doriae), inhibited hNaV 1.7 with a high level of selectivity over all other subtypes, except hNaV 1.1. We showed that Hd1a is a gating modifier that inhibits hNaV 1.7 by interacting with the S3b-S4 paddle motif in channel domain II. The structure of Hd1a, determined using heteronuclear NMR, contains an inhibitor cystine knot motif that is likely to confer high levels of chemical, thermal and biological stability. CONCLUSION AND IMPLICATIONS: Our data indicate that spider venoms are a rich natural source of hNaV 1.7 inhibitors that might be useful leads for the development of novel analgesics. | |||
Seven novel modulators of the analgesic target Na 1.7 uncovered using a high-throughput venom-based discovery approach.,Klint JK, Smith JJ, Vetter I, Rupasinghe DB, Er SY, Senff S, Herzig V, Mobli M, Lewis RJ, Bosmans F, King GF Br J Pharmacol. 2015 Mar 4. doi: 10.1111/bph.13081. PMID:25754331<ref>PMID:25754331</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2mpq" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Haplopelma]] | |||
[[Category: Large Structures]] | |||
[[Category: King GF]] | |||
[[Category: Klint JK]] | |||
[[Category: Mobli M]] | |||
Latest revision as of 09:12, 27 November 2024
Solution structure of the sodium channel toxin Hd1aSolution structure of the sodium channel toxin Hd1a
Structural highlights
Publication Abstract from PubMedBACKGROUND AND PURPOSE: Chronic pain is a serious worldwide health issue, with current analgesics having limited efficacy and dose-limiting side effects. Humans with loss-of-function mutations in the voltage-gated sodium channel NaV 1.7 (hNaV 1.7) are indifferent to pain, making hNaV 1.7 a promising target for analgesic development. Since spider venoms are replete with NaV channel modulators, we examined their potential as a source of hNaV 1.7 inhibitors. EXPERIMENTAL APPROACH: We developed a high-throughput fluorescent-based assay to screen spider venoms against hNaV 1.7 and isolate 'hit' peptides. To examine the binding site of these peptides, we constructed a panel of chimeric channels in which the S3b-S4 paddle motif from each voltage sensor domain of hNaV 1.7 was transplanted into the homotetrameric KV 2.1 channel. KEY RESULTS: We screened 205 spider venoms and found that 40% contain at least one inhibitor of hNaV 1.7. By deconvoluting 'hit' venoms, we discovered seven novel members of the NaSpTx family 1. One of these peptides, Hd1a (peptide mu-TRTX-Hd1a from venom of the spider Haplopelma doriae), inhibited hNaV 1.7 with a high level of selectivity over all other subtypes, except hNaV 1.1. We showed that Hd1a is a gating modifier that inhibits hNaV 1.7 by interacting with the S3b-S4 paddle motif in channel domain II. The structure of Hd1a, determined using heteronuclear NMR, contains an inhibitor cystine knot motif that is likely to confer high levels of chemical, thermal and biological stability. CONCLUSION AND IMPLICATIONS: Our data indicate that spider venoms are a rich natural source of hNaV 1.7 inhibitors that might be useful leads for the development of novel analgesics. Seven novel modulators of the analgesic target Na 1.7 uncovered using a high-throughput venom-based discovery approach.,Klint JK, Smith JJ, Vetter I, Rupasinghe DB, Er SY, Senff S, Herzig V, Mobli M, Lewis RJ, Bosmans F, King GF Br J Pharmacol. 2015 Mar 4. doi: 10.1111/bph.13081. PMID:25754331[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||