8phi - Revision history

OCA at 07:35, 21 November 2024

2024-11-21T07:35:15Z

← Older revision		Revision as of 07:35, 21 November 2024
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	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/~~W8RJF9_HRSV W8RJF9_HRSV~~]		[https://www.uniprot.org/uniprot/FUS_HRSVA FUS_HRSVA] Class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the heptad repeat (HR) regions assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and plasma cell membranes. Directs fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (protein F) interacts with glycoprotein G at the virion surface. Upon binding of G to heparan sulfate, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between host cell and virion membranes. Notably, RSV fusion protein is able to interact directly with heparan sulfate and therefore actively participates in virus attachment. Furthermore, the F2 subunit was identifed as the major determinant of RSV host cell specificity. Later in infection, proteins F expressed at the plasma membrane of infected cells mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53-dependent apoptosis.<ref>PMID:12663767</ref> <ref>PMID:18216092</ref>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC(50): 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

			Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor.,Sake SM, Zhang X, Rajak MK, Urbanek-Quaing M, Carpentier A, Gunesch AP, Grethe C, Matthaei A, Ruckert J, Galloux M, Larcher T, Le Goffic R, Hontonnou F, Chatterjee AK, Johnson K, Morwood K, Rox K, Elgaher WAM, Huang J, Wetzke M, Hansen G, Fischer N, Eleouet JF, Rameix-Welti MA, Hirsch AKH, Herold E, Empting M, Lauber C, Schulz TF, Krey T, Haid S, Pietschmann T Nat Commun. 2024 Feb 8;15(1):1173. doi: 10.1038/s41467-024-45241-y. PMID:38332002<ref>PMID:38332002</ref>

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

OCA at 08:56, 21 February 2024

2024-02-21T08:56:38Z

← Older revision		Revision as of 08:56, 21 February 2024
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	~~'''Unreleased structure'''~~

	~~The entry 8phi is ON HOLD until Paper Publication~~		==Crystal structure of prefusion-stabilized RSV F Variant DS-Cav1 in complex with Lonafarnib==
			<StructureSection load='8phi' size='340' side='right'caption='[[8phi]], [[Resolution\|resolution]] 2.29Å' scene=''>
	~~Authors: Rajak, M., Krey, T.~~		== Structural highlights ==
			<table><tr><td colspan='2'>[[8phi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_respiratory_syncytial_virus_A2 Human respiratory syncytial virus A2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8PHI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PHI FirstGlance]. <br>
	~~Description:~~ Crystal structure of prefusion-stabilized RSV F Variant DS-Cav1 in complex with Lonafarnib		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.289Å</td></tr>
	[[Category: ~~Unreleased~~ Structures]]		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=336:4-{2-[4-(3,10-DIBROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-B]PYRIDIN-11-YL)PIPERIDIN-1-YL]-2-OXOETHYL}PIPERIDINE-1-CARBOXAMIDE'>336</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PG0:2-(2-METHOXYETHOXY)ETHANOL'>PG0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	[[Category: Krey, T]]		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8phi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8phi OCA], [https://pdbe.org/8phi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8phi RCSB], [https://www.ebi.ac.uk/pdbsum/8phi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8phi ProSAT]</span></td></tr>
	[[Category: Rajak, M]]		</table>
			== Function ==
			[https://www.uniprot.org/uniprot/W8RJF9_HRSV W8RJF9_HRSV]
			__TOC__
			</StructureSection>
			[[Category: Human respiratory syncytial virus A2]]
			[[Category: Large Structures]]
			[[Category: Krey T]]
			[[Category: Rajak M]]

OCA at 09:02, 2 August 2023

2023-08-02T09:02:49Z

← Older revision		Revision as of 09:02, 2 August 2023
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	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Rajak, M., Krey, T.		Authors: Rajak, M., Krey, T.

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

2023-06-28T19:52:10Z

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

← Older revision	Revision as of 19:52, 28 June 2023
(No difference)

OCA: New page: '''Unreleased structure''' The entry 8phi is ON HOLD Authors: Rajak, M., Krey, T. Description: Crystal structure of prefusion-stabilized RSV F Variant DS-Cav1 in complex with Lonafarni...

2023-06-28T19:52:09Z

New page: '''Unreleased structure''' The entry 8phi is ON HOLD Authors: Rajak, M., Krey, T. Description: Crystal structure of prefusion-stabilized RSV F Variant DS-Cav1 in complex with Lonafarni...

New page

'''Unreleased structure'''

The entry 8phi is ON HOLD

Authors: Rajak, M., Krey, T.

Description: Crystal structure of prefusion-stabilized RSV F Variant DS-Cav1 in complex with Lonafarnib
[[Category: Unreleased Structures]]
[[Category: Krey, T]]
[[Category: Rajak, M]]