OCA at 05:48, 5 July 2023

OCA — Wed, 05 Jul 2023 05:48:51 GMT

←Older revision		Revision as of 05:48, 5 July 2023
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-	'''Unreleased structure'''

-	The entry ~~8t1d~~ is ~~ON HOLD~~	+	==Open-state cryo-EM structure of full-length human TRPV4 in complex with agonist 4a-PDD==
		+	<StructureSection load='8t1d' size='340' side='right'caption='[[8t1d]], [[Resolution\|resolution]] 3.35Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8t1d]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_betaherpesvirus_5 Human betaherpesvirus 5]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8T1D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8T1D 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]] 3.35Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XS9:(1aR,1bS,4aS,7aS,7bS,8R,9R,9aS)-9a-(decanoyloxy)-4a,7b-dihydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-5-oxo-1a,1b,4,4a,5,7a,7b,8,9,9a-decahydro-1H-cyclopropa[3,4]benzo[1,2-e]azulen-9-yl+decanoate'>XS9</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=8t1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8t1d OCA], [https://pdbe.org/8t1d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8t1d RCSB], [https://www.ebi.ac.uk/pdbsum/8t1d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8t1d ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/TRPV4_HUMAN TRPV4_HUMAN] Spondylometaphyseal dysplasia, Kozlowski type;Familial digital arthropathy-brachydactyly;Autosomal dominant brachyolmia;Autosomal dominant congenital benign spinal muscular atrophy;Parastremmatic dwarfism;Spondyloepiphyseal dysplasia, Maroteaux type;Autosomal dominant Charcot-Marie-Tooth disease type 2C;Metatropic dysplasia. 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. 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/TRPV4_HUMAN TRPV4_HUMAN] Non-selective calcium permeant cation channel probably involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by low pH, citrate and phorbol esters. Increase of intracellular Ca(2+) potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism. Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers. Acts as a regulator of intracellular Ca(2+) in synoviocytes. Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8.<ref>PMID:11025659</ref> <ref>PMID:12724311</ref> <ref>PMID:19759329</ref> [https://www.uniprot.org/uniprot/C5MKY7_HCMV C5MKY7_HCMV]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4alpha-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a pi-to-alpha transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases.

-	~~Authors~~:	+	Structure of human TRPV4 in complex with GTPase RhoA.,Nadezhdin KD, Talyzina IA, Parthasarathy A, Neuberger A, Zhang DX, Sobolevsky AI Nat Commun. 2023 Jun 23;14(1):3733. doi: 10.1038/s41467-023-39346-z. PMID:37353478<ref>PMID:37353478</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 8t1d" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Human betaherpesvirus 5]]
		+	[[Category: Large Structures]]
		+	[[Category: Nadezhdin KD]]
		+	[[Category: Neuberger A]]
		+	[[Category: Sobolevsky AI]]
		+	[[Category: Talyzina IA]]

OCA: Protected "8t1d" [edit=sysop:move=sysop]

OCA — Wed, 14 Jun 2023 06:49:19 GMT

Protected "8t1d" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:49, 14 June 2023

OCA: New page: '''Unreleased structure''' The entry 8t1d is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 14 Jun 2023 06:49:16 GMT

New page: '''Unreleased structure''' The entry 8t1d is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 8t1d is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

8t1d - Revision history

OCA at 05:48, 5 July 2023

OCA: Protected "8t1d" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8t1d is ON HOLD Authors: Description: Category: Unreleased Structures