6n4i - Revision history

OCA at 06:44, 11 October 2023

2023-10-11T06:44:49Z

←Older revision		Revision as of 06:44, 11 October 2023
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	==Structural basis of Nav1.7 inhibition by a gating-modifier spider toxin==		==Structural basis of Nav1.7 inhibition by a gating-modifier spider toxin==
-	<StructureSection load='6n4i' size='340' side='right' caption='[[6n4i]], [[Resolution\|resolution]] 3.54Å' scene=''>	+	<StructureSection load='6n4i' size='340' side='right'caption='[[6n4i]], [[Resolution\|resolution]] 3.54Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6n4i]] is a 8 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~] and [~~http~~://en.wikipedia.org/wiki/~~Peruvian_green_velvet_tarantula Peruvian green velvet tarantula~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N4I OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6N4I FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6n4i]] is a 8 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=6N4I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N4I FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6OU:[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl]+(~{Z})-octadec-9-enoate'>6OU</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 3.541Å</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=6n4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n4i OCA], [~~http~~://pdbe.org/6n4i PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6n4i RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6n4i PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6n4i ProSAT]</span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6OU:[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl]+(~{Z})-octadec-9-enoate'>6OU</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=6n4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n4i OCA], [https://pdbe.org/6n4i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n4i RCSB], [https://www.ebi.ac.uk/pdbsum/6n4i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n4i ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/TXPR2_THRPR TXPR2_THRPR]] Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. Does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2/SCN2A prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. Binds to phospholipids.<ref>PMID:12475222</ref> <ref>PMID:17087985</ref> <ref>PMID:17339321</ref> <ref>PMID:18156314</ref> <ref>PMID:18657562</ref> <ref>PMID:18728100</ref>	+	[https://www.uniprot.org/uniprot/TXPR2_THRPR TXPR2_THRPR] Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. Does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2/SCN2A prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. Binds to phospholipids.<ref>PMID:12475222</ref> <ref>PMID:17087985</ref> <ref>PMID:17339321</ref> <ref>PMID:18156314</ref> <ref>PMID:18657562</ref> <ref>PMID:18728100</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: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Peruvian green velvet tarantula~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Koth, C M~~]]	+	[[Category: Thrixopelma pruriens]]
-	[[Category: ~~Payandeh, J~~]]	+	[[Category: Koth CM]]
-	[[Category: ~~Xu, H~~]]	+	[[Category: Payandeh J]]
-	[[Category: ~~Gating-modifier]]~~	+	[[Category: Xu H]]
-	~~[[Category: Metal transport]]~~	+
-	~~[[Category: Sodium channel]]~~	+
-	~~[[Category: Toxin]]~~	+
-	~~[[Category: Voltage-gated~~]]	+

OCA at 08:49, 21 February 2019

2019-02-21T08:49:27Z

←Older revision		Revision as of 08:49, 21 February 2019
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-	'''Unreleased structure'''

-	~~The entry~~ 6n4i is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Structural basis of Nav1.7 inhibition by a gating-modifier spider toxin==
		+	<StructureSection load='6n4i' size='340' side='right' caption='[[6n4i]], [[Resolution\|resolution]] 3.54Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6n4i]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Peruvian_green_velvet_tarantula Peruvian green velvet tarantula]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N4I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N4I FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6OU:[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl]+(~{Z})-octadec-9-enoate'>6OU</scene></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=6n4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n4i OCA], [http://pdbe.org/6n4i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n4i RCSB], [http://www.ebi.ac.uk/pdbsum/6n4i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n4i ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/TXPR2_THRPR TXPR2_THRPR]] Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. Does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2/SCN2A prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. Binds to phospholipids.<ref>PMID:12475222</ref> <ref>PMID:17087985</ref> <ref>PMID:17339321</ref> <ref>PMID:18156314</ref> <ref>PMID:18657562</ref> <ref>PMID:18728100</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Voltage-gated sodium (Nav) channels are targets of disease mutations, toxins, and therapeutic drugs. Despite recent advances, the structural basis of voltage sensing, electromechanical coupling, and toxin modulation remains ill-defined. Protoxin-II (ProTx2) from the Peruvian green velvet tarantula is an inhibitor cystine-knot peptide and selective antagonist of the human Nav1.7 channel. Here, we visualize ProTx2 in complex with voltage-sensor domain II (VSD2) from Nav1.7 using X-ray crystallography and cryoelectron microscopy. Membrane partitioning orients ProTx2 for unfettered access to VSD2, where ProTx2 interrogates distinct features of the Nav1.7 receptor site. ProTx2 positions two basic residues into the extracellular vestibule to antagonize S4 gating-charge movement through an electrostatic mechanism. ProTx2 has trapped activated and deactivated states of VSD2, revealing a remarkable approximately 10 A translation of the S4 helix, providing a structural framework for activation gating in voltage-gated ion channels. Finally, our results deliver key templates to design selective Nav channel antagonists.

-	~~Authors~~:	+	Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin.,Xu H, Li T, Rohou A, Arthur CP, Tzakoniati F, Wong E, Estevez A, Kugel C, Franke Y, Chen J, Ciferri C, Hackos DH, Koth CM, Payandeh J Cell. 2019 Feb 7;176(4):702-715.e14. doi: 10.1016/j.cell.2018.12.018. Epub 2019, Jan 17. PMID:30661758<ref>PMID:30661758</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 6n4i" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Peruvian green velvet tarantula]]
		+	[[Category: Koth, C M]]
		+	[[Category: Payandeh, J]]
		+	[[Category: Xu, H]]
		+	[[Category: Gating-modifier]]
		+	[[Category: Metal transport]]
		+	[[Category: Sodium channel]]
		+	[[Category: Toxin]]
		+	[[Category: Voltage-gated]]

OCA at 05:19, 12 December 2018

2018-12-12T05:19:42Z

←Older revision		Revision as of 05:19, 12 December 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6n4i is ON HOLD	+	The entry 6n4i is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "6n4i" [edit=sysop:move=sysop]

2018-12-02T19:15:45Z

Protected "6n4i" [edit=sysop:move=sysop]

←Older revision

Revision as of 19:15, 2 December 2018

OCA: New page: '''Unreleased structure''' The entry 6n4i is ON HOLD Authors: Description: Category: Unreleased Structures

2018-12-02T19:15:43Z

New page: '''Unreleased structure''' The entry 6n4i is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6n4i is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]