7saw - Revision history

OCA at 11:20, 14 June 2023

OCA — Wed, 14 Jun 2023 11:20:40 GMT

←Older revision		Revision as of 11:20, 14 June 2023
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	<StructureSection load='7saw' size='340' side='right'caption='[[7saw]]' scene=''>		<StructureSection load='7saw' size='340' side='right'caption='[[7saw]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full ~~crystallographic~~ information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SAW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SAW FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7saw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_kinoshitai Conus kinoshitai]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SAW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SAW FirstGlance]. <br>
-	</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=7saw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7saw OCA], [https://pdbe.org/7saw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7saw RCSB], [https://www.ebi.ac.uk/pdbsum/7saw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7saw ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=7saw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7saw OCA], [https://pdbe.org/7saw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7saw RCSB], [https://www.ebi.ac.uk/pdbsum/7saw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7saw ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/CM3A_CONKI CM3A_CONKI] Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks rNav1.2/SCN2A and rNav1.4/SCN4A. It also moderately blocks rNav1.1/SCN1A, rNav1.3/SCN3A, rNav1.5/SCN5A, mNav1.6/SCN8A, and rNav1.7/SCN9A. On rNav1.2/SCN2A, it produces a block that is only partially reversible. The block of SCN9A is modified when beta-subunits are coexpressed with the alpha subunit. Hence, blocks of channels containing beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing beta-2 and beta-4 subunits are less potent (compared to channels without beta subunits).<ref>PMID:15882064</ref> <ref>PMID:17724025</ref> <ref>PMID:18950653</ref> <ref>PMID:21652775</ref> <ref>PMID:21709136</ref> <ref>PMID:21781281</ref> <ref>PMID:23146020</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	mu-Conotoxins are components of cone snail venom, well-known for their analgesic activity through potent inhibition of voltage-gated sodium channel (NaV) subtypes, including NaV1.7. These small, disulfide-rich peptides are typically stabilized by three disulfide bonds arranged in a 'native' CysI-CysIV, CysII-CysV, CysIII-CysVI pattern of disulfide connectivity. However, mu-conotoxin KIIIA, the smallest and most studied mu-conotoxin with inhibitory activity at NaV1.7, forms two distinct disulfide bond isomers during thermodynamic oxidative folding, including Isomer 1 (CysI-CysV, CysII-CysIV, CysIII-CysVI) and Isomer 2 (CysI-CysVI, CysII-CysIV, CysIII-CysV), but not the native mu-conotoxin arrangement. To date, there has been no study on the structure and activity of KIIIA comprising the native mu-conotoxin disulfide bond arrangement. Here, we evaluated the synthesis, potency, sodium channel subtype selectivity, and 3D structure of the three isomers of KIIIA. Using a regioselective disulfide bond-forming strategy, we synthetically produced the three mu-conotoxin KIIIA isomers displaying distinct bioactivity and NaV subtype selectivity across human NaV channel subtypes 1.2, 1.4, and 1.7. We show that Isomer 1 inhibits NaV subtypes with a rank order of potency of NaV1.4 > 1.2 > 1.7 and Isomer 2 in the order of NaV1.4 approximately 1.2 > 1.7, while the native isomer inhibited NaV1.4 > 1.7 approximately 1.2. The three KIIIA isomers were further evaluated by NMR solution structure analysis and molecular docking with hNaV1.2. Our study highlights the importance of investigating alternate disulfide isomers, as disulfide connectivity affects not only the overall structure of the peptides but also the potency and subtype selectivity of mu-conotoxins targeting therapeutically relevant NaV subtypes.
		+
		+	Structural and functional insights into the inhibition of human voltage-gated sodium channels by mu-conotoxin KIIIA disulfide isomers.,Tran HNT, McMahon KL, Deuis JR, Vetter I, Schroeder CI J Biol Chem. 2022 Mar;298(3):101728. doi: 10.1016/j.jbc.2022.101728. Epub 2022, Feb 12. PMID:35167877<ref>PMID:35167877</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7saw" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Conus kinoshitai]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Schroeder CI]]		[[Category: Schroeder CI]]
	[[Category: Tran HNT]]		[[Category: Tran HNT]]

OCA at 07:59, 25 May 2022

OCA — Wed, 25 May 2022 07:59:11 GMT

←Older revision		Revision as of 07:59, 25 May 2022
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-	'''Unreleased structure'''

-	~~The entry~~ 7saw ~~is ON HOLD until Paper Publication~~	+	==Mu-conotoxin KIIIA isomer 2==
-		+	<StructureSection load='7saw' size='340' side='right'caption='[[7saw]]' scene=''>
-	~~Authors~~: ~~Schroeder~~, C.I., ~~Tran~~, H.N.T.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SAW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SAW FirstGlance]. <br>
-	~~Description~~: Mu-~~conotoxin KIIIA isomer 2~~	+	</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=7saw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7saw OCA], [https://pdbe.org/7saw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7saw RCSB], [https://www.ebi.ac.uk/pdbsum/7saw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7saw ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Schroeder~~, C.I~~]]	+	__TOC__
-	[[Category: Tran~~, H.N.T~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Schroeder CI]]
		+	[[Category: Tran HNT]]

OCA at 04:13, 6 October 2021

OCA — Wed, 06 Oct 2021 04:13:59 GMT

←Older revision		Revision as of 04:13, 6 October 2021
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7saw is ON HOLD	+	The entry 7saw is ON HOLD until Paper Publication

	Authors: Schroeder, C.I., Tran, H.N.T.		Authors: Schroeder, C.I., Tran, H.N.T.
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	Description: Mu-conotoxin KIIIA isomer 2		Description: Mu-conotoxin KIIIA isomer 2
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Tran, H.N.T]]
	[[Category: Schroeder, C.I]]		[[Category: Schroeder, C.I]]
		+	[[Category: Tran, H.N.T]]

OCA: Protected "7saw" [edit=sysop:move=sysop]

OCA — Wed, 29 Sep 2021 07:51:08 GMT

Protected "7saw" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:51, 29 September 2021

OCA: New page: '''Unreleased structure''' The entry 7saw is ON HOLD Authors: Schroeder, C.I., Tran, H.N.T. Description: Mu-conotoxin KIIIA isomer 2 Category: Unreleased Structures [[Category: Tra...

OCA — Wed, 29 Sep 2021 07:51:06 GMT

New page: '''Unreleased structure''' The entry 7saw is ON HOLD Authors: Schroeder, C.I., Tran, H.N.T. Description: Mu-conotoxin KIIIA isomer 2 Category: Unreleased Structures [[Category: Tra...

New page

'''Unreleased structure'''

The entry 7saw is ON HOLD

Authors: Schroeder, C.I., Tran, H.N.T.

Description: Mu-conotoxin KIIIA isomer 2
[[Category: Unreleased Structures]]
[[Category: Tran, H.N.T]]
[[Category: Schroeder, C.I]]