OCA at 05:58, 11 October 2023

OCA — Wed, 11 Oct 2023 05:58:28 GMT

←Older revision		Revision as of 05:58, 11 October 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8h51 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Double Mutant (T21I and E166V) in Complex with Inhibitor Nirmatrelvir==
		+	<StructureSection load='8h51' size='340' side='right'caption='[[8h51]], [[Resolution\|resolution]] 2.18Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8h51]] 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=8H51 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8H51 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]] 2.18Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4WI:(1R,2S,5S)-N-{(1E,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide'>4WI</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=8h51 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8h51 OCA], [https://pdbe.org/8h51 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8h51 RCSB], [https://www.ebi.ac.uk/pdbsum/8h51 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8h51 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/R1A_SARS2 R1A_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]. Also able to bind an ADP-ribose-1''-phosphate (ADRP).[UniProtKB:P0C6X7] 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]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Nirmatrelvir is a specific antiviral drug that targets the main protease (M(pro)) of SARS-CoV-2 and has been approved to treat COVID-19(1,2). As an RNA virus characterized by high mutation rates, whether SARS-CoV-2 will develop resistance to nirmatrelvir is a question of concern. Our previous studies have shown that several mutational pathways confer resistance to nirmatrelvir, but some result in a loss of viral replicative fitness, which is then compensated for by additional alterations(3). The molecular mechanisms for this observed resistance are unknown. Here we combined biochemical and structural methods to demonstrate that alterations at the substrate-binding pocket of M(pro) can allow SARS-CoV-2 to develop resistance to nirmatrelvir in two distinct ways. Comprehensive studies of the structures of 14 M(pro) mutants in complex with drugs or substrate revealed that alterations at the S1 and S4 subsites substantially decreased the level of inhibitor binding, whereas alterations at the S2 and S4' subsites unexpectedly increased protease activity. Both mechanisms contributed to nirmatrelvir resistance, with the latter compensating for the loss in enzymatic activity of the former, which in turn accounted for the restoration of viral replicative fitness, as observed previously(3). Such a profile was also observed for ensitrelvir, another clinically relevant M(pro) inhibitor. These results shed light on the mechanisms by which SARS-CoV-2 evolves to develop resistance to the current generation of protease inhibitors and provide the basis for the design of next-generation M(pro) inhibitors.

-	~~Authors: Lin~~, M., Liu, X.	+	Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir.,Duan Y, Zhou H, Liu X, Iketani S, Lin M, Zhang X, Bian Q, Wang H, Sun H, Hong SJ, Culbertson B, Mohri H, Luck MI, Zhu Y, Liu X, Lu Y, Yang X, Yang K, Sabo Y, Chavez A, Goff SP, Rao Z, Ho DD, Yang H Nature. 2023 Sep 11. doi: 10.1038/s41586-023-06609-0. PMID:37696289<ref>PMID:37696289</ref>

-	~~Description: Crystal Structure~~ of ~~SARS~~-~~CoV~~-~~2 Main Protease (Mpro) Double Mutant (T21I and E166V) in Complex with Inhibitor Nirmatrelvir~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Liu, X~~]]	+	<div class="pdbe-citations 8h51" style="background-color:#fffaf0;"></div>
-	[[Category: Lin, M]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Severe acute respiratory syndrome coronavirus 2]]
		+	[[Category: Lin M]]
		+	[[Category: Liu X]]

OCA at 18:23, 16 November 2022

OCA — Wed, 16 Nov 2022 18:23:29 GMT

←Older revision		Revision as of 18:23, 16 November 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8h51 is ON HOLD	+	The entry 8h51 is ON HOLD until Paper Publication

	Authors: Lin, M., Liu, X.		Authors: Lin, M., Liu, X.
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	Description: Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Double Mutant (T21I and E166V) in Complex with Inhibitor Nirmatrelvir		Description: Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Double Mutant (T21I and E166V) in Complex with Inhibitor Nirmatrelvir
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Lin, M]]
	[[Category: Liu, X]]		[[Category: Liu, X]]
		+	[[Category: Lin, M]]

OCA: Protected "8h51" [edit=sysop:move=sysop]

OCA — Wed, 19 Oct 2022 17:50:30 GMT

Protected "8h51" [edit=sysop:move=sysop]

←Older revision

Revision as of 17:50, 19 October 2022

OCA: New page: '''Unreleased structure''' The entry 8h51 is ON HOLD Authors: Lin, M., Liu, X. Description: Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Double Mutant (T21I and E166V) in Compl...

OCA — Wed, 19 Oct 2022 17:50:29 GMT

New page: '''Unreleased structure''' The entry 8h51 is ON HOLD Authors: Lin, M., Liu, X. Description: Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Double Mutant (T21I and E166V) in Compl...

New page

'''Unreleased structure'''

The entry 8h51 is ON HOLD

Authors: Lin, M., Liu, X.

Description: Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Double Mutant (T21I and E166V) in Complex with Inhibitor Nirmatrelvir
[[Category: Unreleased Structures]]
[[Category: Lin, M]]
[[Category: Liu, X]]

8h51 - Revision history

OCA at 05:58, 11 October 2023

OCA at 18:23, 16 November 2022

OCA: Protected "8h51" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8h51 is ON HOLD Authors: Lin, M., Liu, X. Description: Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Double Mutant (T21I and E166V) in Compl...