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| | ==Solution structure of mu-SLPTX3-Ssm6a== | | ==Solution structure of mu-SLPTX3-Ssm6a== |
| - | <StructureSection load='2mun' size='340' side='right' caption='[[2mun]], [[NMR_Ensembles_of_Models | 25 NMR models]]' scene=''> | + | <StructureSection load='2mun' size='340' side='right'caption='[[2mun]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2mun]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MUN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2MUN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2mun]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Scolopendra_subspinipes Scolopendra subspinipes]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MUN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MUN FirstGlance]. <br> |
| - | </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=2mun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mun OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2mun RCSB], [http://www.ebi.ac.uk/pdbsum/2mun PDBsum]</span></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'>[https://proteopedia.org/fgij/fg.htm?mol=2mun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mun OCA], [https://pdbe.org/2mun PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mun RCSB], [https://www.ebi.ac.uk/pdbsum/2mun PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mun ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TX32A_SCOMU TX32A_SCOMU] Gating-modifier toxin that inhibits voltage-gated sodium channel with a preference for hNav1.7/SCN9A (IC(50)=25.4 nM) over hNav1.1/SCN1A (IC(50)=4.1 uM), hNav1.2/SCN2A (IC(50)=813 nM), and hNav1.6/SCN8A (IC(50)=15.2 uM) (PubMed:24082113). Is an effective analgesic in rodent pain models, since it is several-fold more effective than morphine in a rodent model of formalin-induced pain and is equipotent with morphine in its ability to reduce thermal and acid-induced pain (PubMed:24082113). In addition, this peptide shows a high level of resistance to proteases and a high thermal stability that may be explained by its predominant composition of alpha-helices (PubMed:24082113).<ref>PMID:24082113</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | Loss-of-function mutations in the human voltage-gated sodium channel NaV1.7 result in a congenital indifference to pain. Selective inhibitors of NaV1.7 are therefore likely to be powerful analgesics for treating a broad range of pain conditions. Herein we describe the identification of micro-SLPTX-Ssm6a, a unique 46-residue peptide from centipede venom that potently inhibits NaV1.7 with an IC50 of approximately 25 nM. micro-SLPTX-Ssm6a has more than 150-fold selectivity for NaV1.7 over all other human NaV subtypes, with the exception of NaV1.2, for which the selectivity is 32-fold. micro-SLPTX-Ssm6a contains three disulfide bonds with a unique connectivity pattern, and it has no significant sequence homology with any previously characterized peptide or protein. micro-SLPTX-Ssm6a proved to be a more potent analgesic than morphine in a rodent model of chemical-induced pain, and it was equipotent with morphine in rodent models of thermal and acid-induced pain. This study establishes micro-SPTX-Ssm6a as a promising lead molecule for the development of novel analgesics targeting NaV1.7, which might be suitable for treating a wide range of human pain pathologies.
| + | Arthropod venoms consist primarily of peptide toxins that are injected into their prey with devastating consequences. Venom proteins are thought to be recruited from endogenous body proteins and mutated to yield neofunctionalized toxins with remarkable affinity for specific subtypes of ion channels and receptors. However, the evolutionary history of venom peptides remains poorly understood. Here we show that a neuropeptide hormone has been convergently recruited into the venom of spiders and centipedes and evolved into a highly stable toxin through divergent modification of the ancestral gene. High-resolution structures of representative hormone-derived toxins revealed they possess a unique structure and disulfide framework and that the key structural adaptation in weaponization of the ancestral hormone was loss of a C-terminal alpha helix, an adaptation that occurred independently in spiders and centipedes. Our results raise a new paradigm for toxin evolution and highlight the value of structural information in providing insight into protein evolution. |
| | | | |
| - | Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models.,Yang S, Xiao Y, Kang D, Liu J, Li Y, Undheim EA, Klint JK, Rong M, Lai R, King GF Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17534-9. doi:, 10.1073/pnas.1306285110. Epub 2013 Sep 30. PMID:24082113<ref>PMID:24082113</ref>
| + | Weaponization of a Hormone: Convergent Recruitment of Hyperglycemic Hormone into the Venom of Arthropod Predators.,Undheim EA, Grimm LL, Low CF, Morgenstern D, Herzig V, Zobel-Thropp P, Pineda SS, Habib R, Dziemborowicz S, Fry BG, Nicholson GM, Binford GJ, Mobli M, King GF Structure. 2015 Jun 2. pii: S0969-2126(15)00181-1. doi:, 10.1016/j.str.2015.05.003. PMID:26073605<ref>PMID:26073605</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 2mun" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: King, G F]] | + | [[Category: Large Structures]] |
| - | [[Category: Mobli, M]] | + | [[Category: Scolopendra subspinipes]] |
| - | [[Category: Undheim, E A.B]] | + | [[Category: King GF]] |
| - | [[Category: Crustacean hyperglycemic hormone]] | + | [[Category: Mobli M]] |
| - | [[Category: Ion channel inhibitor]] | + | [[Category: Undheim EAB]] |
| - | [[Category: Mu-slptx-ssm6a]]
| + | |
| - | [[Category: Toxin]]
| + | |
| Structural highlights
Function
TX32A_SCOMU Gating-modifier toxin that inhibits voltage-gated sodium channel with a preference for hNav1.7/SCN9A (IC(50)=25.4 nM) over hNav1.1/SCN1A (IC(50)=4.1 uM), hNav1.2/SCN2A (IC(50)=813 nM), and hNav1.6/SCN8A (IC(50)=15.2 uM) (PubMed:24082113). Is an effective analgesic in rodent pain models, since it is several-fold more effective than morphine in a rodent model of formalin-induced pain and is equipotent with morphine in its ability to reduce thermal and acid-induced pain (PubMed:24082113). In addition, this peptide shows a high level of resistance to proteases and a high thermal stability that may be explained by its predominant composition of alpha-helices (PubMed:24082113).[1]
Publication Abstract from PubMed
Arthropod venoms consist primarily of peptide toxins that are injected into their prey with devastating consequences. Venom proteins are thought to be recruited from endogenous body proteins and mutated to yield neofunctionalized toxins with remarkable affinity for specific subtypes of ion channels and receptors. However, the evolutionary history of venom peptides remains poorly understood. Here we show that a neuropeptide hormone has been convergently recruited into the venom of spiders and centipedes and evolved into a highly stable toxin through divergent modification of the ancestral gene. High-resolution structures of representative hormone-derived toxins revealed they possess a unique structure and disulfide framework and that the key structural adaptation in weaponization of the ancestral hormone was loss of a C-terminal alpha helix, an adaptation that occurred independently in spiders and centipedes. Our results raise a new paradigm for toxin evolution and highlight the value of structural information in providing insight into protein evolution.
Weaponization of a Hormone: Convergent Recruitment of Hyperglycemic Hormone into the Venom of Arthropod Predators.,Undheim EA, Grimm LL, Low CF, Morgenstern D, Herzig V, Zobel-Thropp P, Pineda SS, Habib R, Dziemborowicz S, Fry BG, Nicholson GM, Binford GJ, Mobli M, King GF Structure. 2015 Jun 2. pii: S0969-2126(15)00181-1. doi:, 10.1016/j.str.2015.05.003. PMID:26073605[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yang S, Xiao Y, Kang D, Liu J, Li Y, Undheim EA, Klint JK, Rong M, Lai R, King GF. Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models. Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17534-9. doi:, 10.1073/pnas.1306285110. Epub 2013 Sep 30. PMID:24082113 doi:http://dx.doi.org/10.1073/pnas.1306285110
- ↑ Undheim EA, Grimm LL, Low CF, Morgenstern D, Herzig V, Zobel-Thropp P, Pineda SS, Habib R, Dziemborowicz S, Fry BG, Nicholson GM, Binford GJ, Mobli M, King GF. Weaponization of a Hormone: Convergent Recruitment of Hyperglycemic Hormone into the Venom of Arthropod Predators. Structure. 2015 Jun 2. pii: S0969-2126(15)00181-1. doi:, 10.1016/j.str.2015.05.003. PMID:26073605 doi:http://dx.doi.org/10.1016/j.str.2015.05.003
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