8def - Revision history

OCA at 09:33, 17 October 2024

2024-10-17T09:33:23Z

← Older revision		Revision as of 09:33, 17 October 2024
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	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8def FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8def OCA], [https://pdbe.org/8def PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8def RCSB], [https://www.ebi.ac.uk/pdbsum/8def PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8def ProSAT]</span></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=8def FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8def OCA], [https://pdbe.org/8def PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8def RCSB], [https://www.ebi.ac.uk/pdbsum/8def PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8def ProSAT]</span></td></tr>
	</table>		</table>
	== ~~Function~~ ==		<div style="background-color:#fffaf0;">
	~~[https://www~~.~~uniprot.org/uniprot/POLS_WEEV POLS_WEEV] Forms an icosahedral capsid~~ with a ~~T=4 symmetry composed~~ of ~~240 copies of the capsid protein surrounded by a lipid membrane through which penetrate 80 spikes composed of trimers of E1~~-~~E2 heterodimers~~ (~~By similarity~~)~~. The capsid protein binds to the viral RNA genome at a site adjacent to~~ a ~~ribosome binding site for viral genome translation following genome release (By similarity). Possesses a protease activity~~ that ~~results in its autocatalytic cleavage from the nascent structural protein (By similarity)~~. ~~Following its self~~-~~cleavage, the capsid protein transiently associates with ribosomes~~, and ~~within several minutes the protein binds to viral RNA and rapidly assembles into icosahedric core particles (By similarity)~~. ~~The resulting nucleocapsid eventually associates~~ with ~~the cytoplasmic domain of the spike glycoprotein E2 at the cell membrane, leading to budding~~ and ~~formation of mature virions (By similarity)~~. ~~In case of infection~~, ~~new virions attach~~ to ~~target cells~~ and ~~after clathrin~~-~~mediated endocytosis their membrane fuses with the host endosomal membrane (By similarity). This leads to the release of the nucleocapsid into the cytoplasm, followed~~ by ~~an uncoating event necessary~~ for ~~the genomic RNA to become accessible~~ (~~By similarity)~~. ~~The uncoating might be triggered by the interaction of capsid proteins with ribosomes (By similarity~~). ~~Binding~~ of ~~ribosomes would release the genomic RNA since the same region is genomic RNA~~-~~binding~~ and ~~ribosome-binding (By similarity)~~. ~~Specifically inhibits interleukin-1 receptor-associated kinase 1/IRAK1-dependent signaling during viral entry~~, ~~representing a means by which the alphaviruses may evade innate immune detection and activation prior to viral gene expression (By similarity). Inhibits host transcription (By similarity). Forms~~ a ~~tetrameric complex with XPO1/CRM1 and the nuclear import receptor importin (By similarity). This complex blocks the central channel of host nuclear pores thereby inhibiting the receptor~~-~~mediated nuclear transport and thus the host mRNA and rRNA transcription (By similarity). The inhibition of transcription is linked to~~ a ~~cytopathic effect on the host cell (By similarity).[UniProtKB:P03315][UniProtKB:P03316][UniProtKB:P09592][UniProtKB:P27284][UniProtKB:P36329] Provides the signal sequence for the translocation~~ of ~~the precursor of protein E3/E2 to the host endoplasmic reticulum~~. ~~Furin-cleaved E3 remains associated with spike glycoprotein E1~~ and ~~mediates pH~~ protection ~~of the latter during the transport via the secretory pathway~~. ~~After virion release from the host cell~~, ~~the assembly protein E3 is gradually released in the extracellular space.[UniProtKB:P03315] Plays an essential role in viral attachment to target host cell~~, ~~by binding to the cell receptor. Synthesized as a pE2 precursor which is processed by furin at the cell membrane just before virion budding~~, ~~giving rise to E2-E1 heterodimer. The pE2-E1 heterodimer is stable~~, ~~whereas E2-E1 is unstable and dissociate at low pH. pE2 is processed at the last step~~, ~~presumably to avoid E1 fusion activation before its final export to cell surface. E2 C-terminus contains a transitory transmembrane that would be disrupted by palmitoylation~~, resulting in reorientation of the C-terminal tail from lumenal to cytoplasmic side. This step is critical since E2 C-terminus is involved in budding by interacting with capsid proteins. This release of E2 C-terminus in cytoplasm occurs lately in protein export, ~~and precludes premature assembly of particles at the endoplasmic reticulum membrane.[UniProtKB:P03316] Protein 6K: Acts as a viroporin that participates in virus glycoprotein processing~~, ~~cell permeabilization and budding of viral particles. Disrupts the calcium homeostasis of the cell~~, ~~probably at the endoplasmic reticulum level resulting in the increased levels of cytoplasmic calcium. Because of its lipophilic properties~~, ~~the 6K protein is postulated to influence the selection of lipids that interact with the transmembrane domains of the glycoproteins~~, ~~which~~, ~~in turn~~, ~~affects the deformability of the bilayer required for the extreme curvature that occurs as budding proceeds~~. ~~Present in low amount in virions, about 3% compared to viral glycoproteins~~.~~[UniProtKB~~:~~P03316] Class II viral fusion protein~~. ~~Fusion activity is inactive as long as E1 is bound to E2 in mature virion~~. ~~After virus attachment to target~~ cell ~~and endocytosis~~, ~~acidification of the endosome would induce dissociation of E1~~/~~E2 heterodimer and concomitant trimerization~~ of the ~~E1 subunits~~. ~~This E1 trimer is fusion active, and promotes release of viral nucleocapsid in cytoplasm after endosome and viral membrane fusion~~. ~~Efficient fusion requires the presence~~ of ~~cholesterol and sphingolipid in the target membrane~~.~~[UniProtKB~~:~~P03316]~~		== Publication Abstract from PubMed ==
			Alphaviruses are RNA viruses that represent emerging public health threats. To identify protective antibodies, we immunized macaques with a mixture of western, eastern, and Venezuelan equine encephalitis virus-like particles (VLPs), a regimen that protects against aerosol challenge with all three viruses. Single- and triple-virus-specific antibodies were isolated, and we identified 21 unique binding groups. Cryo-EM structures revealed that broad VLP binding inversely correlated with sequence and conformational variability. One triple-specific antibody, SKT05, bound proximal to the fusion peptide and neutralized all three Env-pseudotyped encephalitic alphaviruses by using different symmetry elements for recognition across VLPs. Neutralization in other assays (e.g., chimeric Sindbis virus) yielded variable results. SKT05 bound backbone atoms of sequence-diverse residues, enabling broad recognition despite sequence variability; accordingly, SKT05 protected mice against Venezuelan equine encephalitis virus, chikungunya virus, and Ross River virus challenges. Thus, a single vaccine-elicited antibody can protect in vivo against a broad range of alphaviruses.

			Vaccine elicitation and structural basis for antibody protection against alphaviruses.,Sutton MS, Pletnev S, Callahan V, Ko S, Tsybovsky Y, Bylund T, Casner RG, Cerutti G, Gardner CL, Guirguis V, Verardi R, Zhang B, Ambrozak D, Beddall M, Lei H, Yang ES, Liu T, Henry AR, Rawi R, Schon A, Schramm CA, Shen CH, Shi W, Stephens T, Yang Y, Florez MB, Ledgerwood JE, Burke CW, Shapiro L, Fox JM, Kwong PD, Roederer M Cell. 2023 Jun 8;186(12):2672-2689.e25. doi: 10.1016/j.cell.2023.05.019. Epub , 2023 Jun 8. PMID:37295404<ref>PMID:37295404</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 8def" style="background-color:#fffaf0;"></div>
			== References ==
			<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 05:41, 5 July 2023

2023-07-05T05:41:16Z

← Older revision		Revision as of 05:41, 5 July 2023
Line 1:		Line 1:
	~~'''Unreleased structure'''~~

	~~The entry~~ 8def is ~~ON HOLD until Paper Publication~~		==Cryo-EM Structure of Western Equine Encephalitis Virus VLP in complex with SKW24 fab==
			<StructureSection load='8def' size='340' side='right'caption='[[8def]], [[Resolution\|resolution]] 4.20Å' scene=''>
	~~Authors~~: ~~Pletnev~~, S., ~~Tsybovsky~~, Y., ~~Verardi~~, R., ~~Roedeger~~, M., ~~Kwong~~, P.D.		== Structural highlights ==
			<table><tr><td colspan='2'>[[8def]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Western_equine_encephalitis_virus Western equine encephalitis virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DEF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DEF FirstGlance]. <br>
	~~Description~~: ~~Cryo~~-~~EM Structure~~ of ~~Western Equine Encephalitis Virus VLP~~ in ~~complex~~ with ~~SKW24 fab~~		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution\|Resolution]] 4.2Å</td></tr>
	[[Category: ~~Unreleased~~ Structures]]		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8def FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8def OCA], [https://pdbe.org/8def PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8def RCSB], [https://www.ebi.ac.uk/pdbsum/8def PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8def ProSAT]</span></td></tr>
	[[Category: ~~Roedeger, M~~]]		</table>
	[[Category: Pletnev, S]]		== Function ==
	[[Category: ~~Verardi, R~~]]		[https://www.uniprot.org/uniprot/POLS_WEEV POLS_WEEV] Forms an icosahedral capsid with a T=4 symmetry composed of 240 copies of the capsid protein surrounded by a lipid membrane through which penetrate 80 spikes composed of trimers of E1-E2 heterodimers (By similarity). The capsid protein binds to the viral RNA genome at a site adjacent to a ribosome binding site for viral genome translation following genome release (By similarity). Possesses a protease activity that results in its autocatalytic cleavage from the nascent structural protein (By similarity). Following its self-cleavage, the capsid protein transiently associates with ribosomes, and within several minutes the protein binds to viral RNA and rapidly assembles into icosahedric core particles (By similarity). The resulting nucleocapsid eventually associates with the cytoplasmic domain of the spike glycoprotein E2 at the cell membrane, leading to budding and formation of mature virions (By similarity). In case of infection, new virions attach to target cells and after clathrin-mediated endocytosis their membrane fuses with the host endosomal membrane (By similarity). This leads to the release of the nucleocapsid into the cytoplasm, followed by an uncoating event necessary for the genomic RNA to become accessible (By similarity). The uncoating might be triggered by the interaction of capsid proteins with ribosomes (By similarity). Binding of ribosomes would release the genomic RNA since the same region is genomic RNA-binding and ribosome-binding (By similarity). Specifically inhibits interleukin-1 receptor-associated kinase 1/IRAK1-dependent signaling during viral entry, representing a means by which the alphaviruses may evade innate immune detection and activation prior to viral gene expression (By similarity). Inhibits host transcription (By similarity). Forms a tetrameric complex with XPO1/CRM1 and the nuclear import receptor importin (By similarity). This complex blocks the central channel of host nuclear pores thereby inhibiting the receptor-mediated nuclear transport and thus the host mRNA and rRNA transcription (By similarity). The inhibition of transcription is linked to a cytopathic effect on the host cell (By similarity).[UniProtKB:P03315][UniProtKB:P03316][UniProtKB:P09592][UniProtKB:P27284][UniProtKB:P36329] Provides the signal sequence for the translocation of the precursor of protein E3/E2 to the host endoplasmic reticulum. Furin-cleaved E3 remains associated with spike glycoprotein E1 and mediates pH protection of the latter during the transport via the secretory pathway. After virion release from the host cell, the assembly protein E3 is gradually released in the extracellular space.[UniProtKB:P03315] Plays an essential role in viral attachment to target host cell, by binding to the cell receptor. Synthesized as a pE2 precursor which is processed by furin at the cell membrane just before virion budding, giving rise to E2-E1 heterodimer. The pE2-E1 heterodimer is stable, whereas E2-E1 is unstable and dissociate at low pH. pE2 is processed at the last step, presumably to avoid E1 fusion activation before its final export to cell surface. E2 C-terminus contains a transitory transmembrane that would be disrupted by palmitoylation, resulting in reorientation of the C-terminal tail from lumenal to cytoplasmic side. This step is critical since E2 C-terminus is involved in budding by interacting with capsid proteins. This release of E2 C-terminus in cytoplasm occurs lately in protein export, and precludes premature assembly of particles at the endoplasmic reticulum membrane.[UniProtKB:P03316] Protein 6K: Acts as a viroporin that participates in virus glycoprotein processing, cell permeabilization and budding of viral particles. Disrupts the calcium homeostasis of the cell, probably at the endoplasmic reticulum level resulting in the increased levels of cytoplasmic calcium. Because of its lipophilic properties, the 6K protein is postulated to influence the selection of lipids that interact with the transmembrane domains of the glycoproteins, which, in turn, affects the deformability of the bilayer required for the extreme curvature that occurs as budding proceeds. Present in low amount in virions, about 3% compared to viral glycoproteins.[UniProtKB:P03316] Class II viral fusion protein. Fusion activity is inactive as long as E1 is bound to E2 in mature virion. After virus attachment to target cell and endocytosis, acidification of the endosome would induce dissociation of E1/E2 heterodimer and concomitant trimerization of the E1 subunits. This E1 trimer is fusion active, and promotes release of viral nucleocapsid in cytoplasm after endosome and viral membrane fusion. Efficient fusion requires the presence of cholesterol and sphingolipid in the target membrane.[UniProtKB:P03316]
	[[Category: ~~Kwong, P.D~~]]		__TOC__
	[[Category: ~~Tsybovsky, Y~~]]		</StructureSection>
			[[Category: Homo sapiens]]
			[[Category: Large Structures]]
			[[Category: Western equine encephalitis virus]]
			[[Category: Kwong PD]]
			[[Category: Pletnev S]]
			[[Category: Roedeger M]]
			[[Category: Tsybovsky Y]]
			[[Category: Verardi R]]

OCA at 04:15, 13 July 2022

2022-07-13T04:15:30Z

← Older revision		Revision as of 04:15, 13 July 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 8def is ON HOLD		The entry 8def is ON HOLD until Paper Publication

	Authors: Pletnev, S., Tsybovsky, Y., Verardi, R., Roedeger, M., Kwong, P.D.		Authors: Pletnev, S., Tsybovsky, Y., Verardi, R., Roedeger, M., Kwong, P.D.

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

2022-06-29T06:31:11Z

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

← Older revision	Revision as of 06:31, 29 June 2022
(No difference)

OCA: New page: '''Unreleased structure''' The entry 8def is ON HOLD Authors: Pletnev, S., Tsybovsky, Y., Verardi, R., Roedeger, M., Kwong, P.D. Description: Cryo-EM Structure of Western Equine Enceph...

2022-06-29T06:31:10Z

New page: '''Unreleased structure''' The entry 8def is ON HOLD Authors: Pletnev, S., Tsybovsky, Y., Verardi, R., Roedeger, M., Kwong, P.D. Description: Cryo-EM Structure of Western Equine Enceph...

New page

'''Unreleased structure'''

The entry 8def is ON HOLD

Authors: Pletnev, S., Tsybovsky, Y., Verardi, R., Roedeger, M., Kwong, P.D.

Description: Cryo-EM Structure of Western Equine Encephalitis Virus VLP in complex with SKW24 fab
[[Category: Unreleased Structures]]
[[Category: Roedeger, M]]
[[Category: Pletnev, S]]
[[Category: Verardi, R]]
[[Category: Kwong, P.D]]
[[Category: Tsybovsky, Y]]