OCA at 17:03, 18 October 2023

OCA — Wed, 18 Oct 2023 17:03:12 GMT

←Older revision		Revision as of 17:03, 18 October 2023
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-	====	+	==Co-crystal structure of SARS-CoV-2 Mpro C145A with substrate peptide 13/14==
-	<StructureSection load='7tbt' size='340' side='right'caption='[[7tbt]]' scene=''>	+	<StructureSection load='7tbt' size='340' side='right'caption='[[7tbt]], [[Resolution\|resolution]] 2.45Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7tbt]] is a 2 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=7TBT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TBT FirstGlance]. <br>
-	</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=7tbt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tbt OCA], [https://pdbe.org/7tbt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tbt RCSB], [https://www.ebi.ac.uk/pdbsum/7tbt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tbt ProSAT]</span></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.45Å</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=7tbt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tbt OCA], [https://pdbe.org/7tbt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tbt RCSB], [https://www.ebi.ac.uk/pdbsum/7tbt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tbt ProSAT]</span></td></tr>
	</table>		</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 ==
		+	Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (M(pro)) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 M(pro) bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of M(pro), map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed M(pro) inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.
		+
		+	Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance.,Shaqra AM, Zvornicanin SN, Huang QYJ, Lockbaum GJ, Knapp M, Tandeske L, Bakan DT, Flynn J, Bolon DNA, Moquin S, Dovala D, Kurt Yilmaz N, Schiffer CA Nat Commun. 2022 Jun 21;13(1):3556. doi: 10.1038/s41467-022-31210-w. PMID:35729165<ref>PMID:35729165</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7tbt" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Nonstructural protein 3D structures\|Nonstructural protein 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Severe acute respiratory syndrome coronavirus 2]]
		+	[[Category: Schiffer CA]]
		+	[[Category: Shaqra AM]]

OCA at 09:45, 22 June 2022

OCA — Wed, 22 Jun 2022 09:45:59 GMT

←Older revision		Revision as of 09:45, 22 June 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7tbt ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='7tbt' size='340' side='right'caption='[[7tbt]]' scene=''>
-	~~Authors~~: ~~Shaqra, A~~.M.~~, Schiffer, C~~.A.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
-	~~Description~~: Co-~~crystal structure of SARS-CoV-2 Mpro C145A with substrate peptide 13~~/14	+	</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=7tbt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tbt OCA], [https://pdbe.org/7tbt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tbt RCSB], [https://www.ebi.ac.uk/pdbsum/7tbt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tbt ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[Category: ~~Schiffer, C.A~~]]	+	__TOC__
-	[[Category: ~~Shaqra, A.M~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Z-disk]]

OCA at 09:20, 5 January 2022

OCA — Wed, 05 Jan 2022 09:20:38 GMT

←Older revision		Revision as of 09:20, 5 January 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7tbt is ON HOLD	+	The entry 7tbt is ON HOLD until Paper Publication

	Authors: Shaqra, A.M., Schiffer, C.A.		Authors: Shaqra, A.M., Schiffer, C.A.

OCA: Protected "7tbt" [edit=sysop:move=sysop]

OCA — Wed, 29 Dec 2021 12:11:16 GMT

Protected "7tbt" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:11, 29 December 2021

OCA: New page: '''Unreleased structure''' The entry 7tbt is ON HOLD Authors: Shaqra, A.M., Schiffer, C.A. Description: Co-crystal structure of SARS-CoV-2 Mpro C145A with substrate peptide 13/14 [[Cat...

OCA — Wed, 29 Dec 2021 12:11:15 GMT

New page: '''Unreleased structure''' The entry 7tbt is ON HOLD Authors: Shaqra, A.M., Schiffer, C.A. Description: Co-crystal structure of SARS-CoV-2 Mpro C145A with substrate peptide 13/14 [[Cat...

New page

'''Unreleased structure'''

The entry 7tbt is ON HOLD

Authors: Shaqra, A.M., Schiffer, C.A.

Description: Co-crystal structure of SARS-CoV-2 Mpro C145A with substrate peptide 13/14
[[Category: Unreleased Structures]]
[[Category: Schiffer, C.A]]
[[Category: Shaqra, A.M]]

7tbt - Revision history

OCA at 17:03, 18 October 2023

OCA at 09:45, 22 June 2022

OCA at 09:20, 5 January 2022

OCA: Protected "7tbt" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7tbt is ON HOLD Authors: Shaqra, A.M., Schiffer, C.A. Description: Co-crystal structure of SARS-CoV-2 Mpro C145A with substrate peptide 13/14 [[Cat...