9dbn: Difference between revisions

Latest revision as of 14:54, 19 February 2025

Tarantula venom peptide Protoxin-I bound to full-length human voltage-gated sodium channel 1.8 (NaV1.8)

Structural highlights

9dbn is a 2 chain structure with sequence from Homo sapiens and Thrixopelma pruriens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.76Å
Ligands:	BMA, CLR, LPE, NAG, P5S, PCW
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TXPR1_THRPR Inhibits voltage-gated calcium channels Cav3.1/CACNA1G, voltage-gated potassium channels Kv2.1/KCNB1 and all sodium channels tested (Nav1.2/SCN2A, Nav1.5/SCN5A, Nav1.7/SCN9A, and Nav1.8/SCN10A). Shifts the voltage-dependence of channel activation to more positive potentials. Most potent against Nav1.8/SCN10A.^[1] ^[2]

Publication Abstract from PubMed

Voltage-gated sodium channels (Na(V)s) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human Na(V) isoforms, Na(V)1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarized potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-Na(V)1.8 and the Protoxin-I-bound complex at 3.1 A and 2.8 A resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSD(I) was unresolvable. We find that Protoxin-I binds to and displaces the VSD(II) S3-S4 linker, hindering translocation of the S4(II) helix during activation.

Structural basis of inhibition of human Na(V)1.8 by the tarantula venom peptide Protoxin-I.,Neumann B, McCarthy S, Gonen S Nat Commun. 2025 Feb 7;16(1):1459. doi: 10.1038/s41467-024-55764-z. PMID:39920100^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Middleton RE, Warren VA, Kraus RL, Hwang JC, Liu CJ, Dai G, Brochu RM, Kohler MG, Gao YD, Garsky VM, Bogusky MJ, Mehl JT, Cohen CJ, Smith MM. Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry. 2002 Dec 17;41(50):14734-47. PMID:12475222
↑ Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM. ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon. 2007 Feb;49(2):194-201. Epub 2006 Sep 27. PMID:17087985 doi:https://dx.doi.org/10.1016/j.toxicon.2006.09.014
↑ Neumann B, McCarthy S, Gonen S. Structural basis of inhibition of human Na(V)1.8 by the tarantula venom peptide Protoxin-I. Nat Commun. 2025 Feb 7;16(1):1459. PMID:39920100 doi:10.1038/s41467-024-55764-z

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Middleton RE, Warren VA, Kraus RL, Hwang JC, Liu CJ, Dai G, Brochu RM, Kohler MG, Gao YD, Garsky VM, Bogusky MJ, Mehl JT, Cohen CJ, Smith MM. Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry. 2002 Dec 17;41(50):14734-47. PMID:12475222

[2] Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM. ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon. 2007 Feb;49(2):194-201. Epub 2006 Sep 27. PMID:17087985 doi:https://dx.doi.org/10.1016/j.toxicon.2006.09.014

[3] Neumann B, McCarthy S, Gonen S. Structural basis of inhibition of human Na(V)1.8 by the tarantula venom peptide Protoxin-I. Nat Commun. 2025 Feb 7;16(1):1459. PMID:39920100 doi:10.1038/s41467-024-55764-z

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9dbn is ON HOLD  until Paper Publication
+==Tarantula venom peptide Protoxin-I bound to full-length human voltage-gated sodium channel 1.8 (NaV1.8)==
+<StructureSection load='9dbn' size='340' side='right'caption='[[9dbn]], [[Resolution|resolution]] 2.76&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9dbn]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Thrixopelma_pruriens Thrixopelma pruriens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9DBN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DBN FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.76&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=LPE:1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>LPE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=P5S:O-[(R)-{[(2R)-2,3-BIS(OCTADECANOYLOXY)PROPYL]OXY}(HYDROXY)PHOSPHORYL]-L-SERINE'>P5S</scene>, <scene name='pdbligand=PCW:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PCW</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=9dbn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9dbn OCA], [https://pdbe.org/9dbn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9dbn RCSB], [https://www.ebi.ac.uk/pdbsum/9dbn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9dbn ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/TXPR1_THRPR TXPR1_THRPR] Inhibits voltage-gated calcium channels Cav3.1/CACNA1G, voltage-gated potassium channels Kv2.1/KCNB1 and all sodium channels tested (Nav1.2/SCN2A, Nav1.5/SCN5A, Nav1.7/SCN9A, and Nav1.8/SCN10A). Shifts the voltage-dependence of channel activation to more positive potentials. Most potent against Nav1.8/SCN10A.<ref>PMID:12475222</ref> <ref>PMID:17087985</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Voltage-gated sodium channels (Na(V)s) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human Na(V) isoforms, Na(V)1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarized potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-Na(V)1.8 and the Protoxin-I-bound complex at 3.1 A and 2.8 A resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSD(I) was unresolvable. We find that Protoxin-I binds to and displaces the VSD(II) S3-S4 linker, hindering translocation of the S4(II) helix during activation.
-Authors: Neumann, B., McCarthy, S., Gonen, S.
+Structural basis of inhibition of human Na(V)1.8 by the tarantula venom peptide Protoxin-I.,Neumann B, McCarthy S, Gonen S Nat Commun. 2025 Feb 7;16(1):1459. doi: 10.1038/s41467-024-55764-z. PMID:39920100<ref>PMID:39920100</ref>
-Description: Structure of a human ion channel in complex with an inhibitory peptide
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Gonen, S]]
+<div class="pdbe-citations 9dbn" style="background-color:#fffaf0;"></div>
-[[Category: Mccarthy, S]]
+== References ==
-[[Category: Neumann, B]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Thrixopelma pruriens]]
+[[Category: Gonen S]]
+[[Category: McCarthy S]]
+[[Category: Neumann B]]

9dbn: Difference between revisions

Latest revision as of 14:54, 19 February 2025

Tarantula venom peptide Protoxin-I bound to full-length human voltage-gated sodium channel 1.8 (NaV1.8)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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