OCA at 20:32, 12 April 2023

OCA — Wed, 12 Apr 2023 20:32:17 GMT

←Older revision		Revision as of 20:32, 12 April 2023
Line 1:		Line 1:
-	'''Unreleased structure'''

-	The entry ~~8f0p~~ is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Structure of VSD4-NaV1.7-NaVPas channel chimera bound to the hybrid inhibitor GNE-1305==
		+	<StructureSection load='8f0p' size='340' side='right'caption='[[8f0p]], [[Resolution\|resolution]] 2.20Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8f0p]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Periplaneta_americana Periplaneta americana]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8F0P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8F0P FirstGlance]. <br>
		+	</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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEE:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>PEE</scene>, <scene name='pdbligand=X7L:N-[6-(cyclopentylmethoxy)-1,3-benzothiazol-2-yl]-4-{[(1S,2S)-2-(dimethylamino)cyclohexyl]amino}-2-fluorobenzene-1-sulfonamide'>X7L</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=8f0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8f0p OCA], [https://pdbe.org/8f0p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8f0p RCSB], [https://www.ebi.ac.uk/pdbsum/8f0p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8f0p ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/SCN9A_HUMAN SCN9A_HUMAN] Channelopathy-associated congenital insensitivity to pain;Dravet syndrome;Primary erythromelalgia;Sodium channelopathy-related small fiber neuropathy;Generalized epilepsy with febrile seizures-plus;Hereditary sensory and autonomic neuropathy type 2;Paroxysmal extreme pain disorder;Erythromelalgia. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/SCN9A_HUMAN SCN9A_HUMAN] Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784).<ref>PMID:15178348</ref> <ref>PMID:15385606</ref> <ref>PMID:16988069</ref> <ref>PMID:17145499</ref> <ref>PMID:17167479</ref> <ref>PMID:19369487</ref> <ref>PMID:24311784</ref> <ref>PMID:25240195</ref> <ref>PMID:26680203</ref> <ref>PMID:7720699</ref> [https://www.uniprot.org/uniprot/SCNA1_PERAM SCNA1_PERAM] Mediates the voltage-dependent sodium ion permeability of excitable membranes.[RuleBase:RU361132]<ref>PMID:28183995</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The voltage-gated sodium (Na(V)) channel Na(V)1.7 has been identified as a potential novel analgesic target due to its involvement in human pain syndromes. However, clinically available Na(V) channel blocking drugs are not selective among the nine Na(V) channel subtypes, Na(V)1.1-Na(V)1.9. Moreover, the two currently known classes of Na(V)1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. To this point understanding of the structure-activity relationships of the acylsulfonamide class of Na(V)1.7 inhibitors, exemplified by the clinical development candidate GDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor bound to voltage-sensing domain 4 (VSD4). To advance inhibitor design targeting the Na(V)1.7 channel, we pursued high-resolution ligand-bound Na(V)1.7-VSD4 structures using cryogenic electron microscopy (cryo-EM). Here, we report that GDC-0310 engages the Na(V)1.7-VSD4 through an unexpected binding mode orthogonal to the arylsulfonamide inhibitor class binding pose, which identifies a previously unknown ligand binding site in Na(V) channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl- and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, our study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design This work also underscores an important role of the membrane bilayer in the optimization of selective Na(V) channel modulators targeting VSD4.

-	~~Authors~~:	+	Cryo-EM reveals an unprecedented binding site for Na(V)1.7 inhibitors enabling rational design of potent hybrid inhibitors.,Kschonsak M, Jao CC, Arthur CP, Rohou AL, Bergeron P, Ortwine DF, McKerrall SJ, Hackos DH, Deng L, Chen J, Li T, Dragovich PS, Volgraf M, Wright MR, Payandeh J, Ciferri C, Tellis JC Elife. 2023 Mar 28;12:e84151. doi: 10.7554/eLife.84151. PMID:36975198<ref>PMID:36975198</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 8f0p" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Periplaneta americana]]
		+	[[Category: Arthur CP]]
		+	[[Category: Bergeron P]]
		+	[[Category: Chen J]]
		+	[[Category: Ciferri C]]
		+	[[Category: Deng L]]
		+	[[Category: Dragovich PS]]
		+	[[Category: Hackos DH]]
		+	[[Category: Jao CC]]
		+	[[Category: Kschonsak M]]
		+	[[Category: McKerall SJ]]
		+	[[Category: Ortwine D]]
		+	[[Category: Payandeh J]]
		+	[[Category: Rohou AL]]
		+	[[Category: Sutherlin D]]
		+	[[Category: Tellis JC]]
		+	[[Category: Volgraf M]]
		+	[[Category: Wright MR]]

OCA at 05:30, 7 December 2022

OCA — Wed, 07 Dec 2022 05:30:21 GMT

←Older revision		Revision as of 05:30, 7 December 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8f0p is ON HOLD	+	The entry 8f0p is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "8f0p" [edit=sysop:move=sysop]

OCA — Wed, 09 Nov 2022 05:09:43 GMT

Protected "8f0p" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:09, 9 November 2022

OCA: New page: '''Unreleased structure''' The entry 8f0p is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 09 Nov 2022 05:09:42 GMT

New page: '''Unreleased structure''' The entry 8f0p is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 8f0p is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

8f0p - Revision history

OCA at 20:32, 12 April 2023

OCA at 05:30, 7 December 2022

OCA: Protected "8f0p" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8f0p is ON HOLD Authors: Description: Category: Unreleased Structures