OCA at 05:27, 9 August 2023

2023-08-09T05:27:30Z

←Older revision		Revision as of 05:27, 9 August 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8fiv is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor Jun10541R==
		+	<StructureSection load='8fiv' size='340' side='right'caption='[[8fiv]], [[Resolution\|resolution]] 2.51Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8fiv]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FIV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FIV FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.51Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y0I:(3Z)-N-([1,1-biphenyl]-4-yl)-3-imino-N-[(1R)-2-oxo-2-{[(1S)-1-phenylethyl]amino}-1-(pyridin-3-yl)ethyl]propanamide'>Y0I</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=8fiv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fiv OCA], [https://pdbe.org/8fiv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fiv RCSB], [https://www.ebi.ac.uk/pdbsum/8fiv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fiv ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/R1AB_SARS2 R1AB_SARS2] Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.[UniProtKB:P0C6X7] Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.[UniProtKB:P0C6X7] May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[UniProtKB:P0C6X7] Responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.[UniProtKB:P0C6X7] Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7] Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-\|-[SGACN] (PubMed:32198291). Also able to bind an ADP-ribose-1''-phosphate (ADRP).[UniProtKB:P0C6X7]<ref>PMID:32198291</ref> Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7] Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[UniProtKB:P0C6X7] Responsible for replication and transcription of the viral RNA genome.[UniProtKB:P0C6X7] Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium.[UniProtKB:P0C6X7] Enzyme possessing two different activities: an exoribonuclease activity acting on both ssRNA and dsRNA in a 3' to 5' direction and a N7-guanine methyltransferase activity. Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens.[UniProtKB:P0C6X7] Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.[UniProtKB:P0C6X7] Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs. N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system.[UniProtKB:P0C6X7]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	SARS-CoV-2 main protease (M(pro)) is a validated antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant M(pro) mutants against nirmatrelvir have been identified from cell culture viral passage and naturally occurring variants. As such, there is a need for a second generation of M(pro) inhibitors. In this study, we explored several reactive warheads in the design of M(pro) inhibitors. We identified Jun11119R (vinyl sulfonamide warhead), Jun10221R (propiolamide warhead), Jun1112R (4-chlorobut-2-ynamide warhead), Jun10541R (nitrile warhead), and Jun10963R (dually activated nitrile warhead) as potent M(pro) inhibitors. Jun10541R and Jun10963R also had potent antiviral activity against SARS-CoV-2 in Calu-3 cells with EC(50) values of 2.92 and 6.47 muM, respectively. X-ray crystal structures of M(pro) with Jun10541R and Jun10221 revealed covalent modification of Cys145. These M(pro) inhibitors with diverse reactive warheads collectively represent promising candidates for further development.

-	~~Authors: Sacco~~, M., ~~Wang~~, J., ~~Chen~~, Y.	+	Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors.,Tan B, Sacco M, Tan H, Li K, Joyce R, Zhang X, Chen Y, Wang J Eur J Med Chem. 2023 Jul 19;259:115667. doi: 10.1016/j.ejmech.2023.115667. PMID:37482021<ref>PMID:37482021</ref>

-	~~Description: Crystal structure~~ of the ~~SARS~~-~~CoV~~-~~2 (COVID-19) main protease in complex with inhibitor Jun10-54-1~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Chen, Y~~]]	+	<div class="pdbe-citations 8fiv" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Wang, J~~]]	+	== References ==
-	[[Category: Sacco, M]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Severe acute respiratory syndrome coronavirus 2]]
		+	[[Category: Chen Y]]
		+	[[Category: Sacco M]]
		+	[[Category: Wang J]]

OCA at 04:56, 25 January 2023

2023-01-25T04:56:34Z

←Older revision		Revision as of 04:56, 25 January 2023
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	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Sacco, M., Wang, J., Chen, Y.		Authors: Sacco, M., Wang, J., Chen, Y.

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

2022-12-28T05:56:08Z

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

←Older revision

Revision as of 05:56, 28 December 2022

OCA: New page: '''Unreleased structure''' The entry 8fiv is ON HOLD Authors: Sacco, M., Wang, J., Chen, Y. Description: Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with in...

2022-12-28T05:56:03Z

New page: '''Unreleased structure''' The entry 8fiv is ON HOLD Authors: Sacco, M., Wang, J., Chen, Y. Description: Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with in...

New page

'''Unreleased structure'''

The entry 8fiv is ON HOLD

Authors: Sacco, M., Wang, J., Chen, Y.

Description: Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor Jun10-54-1
[[Category: Unreleased Structures]]
[[Category: Chen, Y]]
[[Category: Wang, J]]
[[Category: Sacco, M]]

8fiv - Revision history

OCA at 05:27, 9 August 2023

OCA at 04:56, 25 January 2023

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

OCA: New page: '''Unreleased structure''' The entry 8fiv is ON HOLD Authors: Sacco, M., Wang, J., Chen, Y. Description: Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with in...