7set - Revision history

OCA at 09:10, 17 October 2024

2024-10-17T09:10:14Z

← Older revision		Revision as of 09:10, 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=7set FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7set OCA], [https://pdbe.org/7set PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7set RCSB], [https://www.ebi.ac.uk/pdbsum/7set PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7set 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=7set FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7set OCA], [https://pdbe.org/7set PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7set RCSB], [https://www.ebi.ac.uk/pdbsum/7set PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7set ProSAT]</span></td></tr>
	</table>		</table>
	== ~~Function~~ ==		<div style="background-color:#fffaf0;">
	~~[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]		== Publication Abstract from PubMed ==
			Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M(pro)) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 M(pro) more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.

			An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations.,Westberg M, Su Y, Zou X, Huang P, Rustagi A, Garhyan J, Patel PB, Fernandez D, Wu Y, Hao C, Lo CW, Karim M, Ning L, Beck A, Saenkham-Huntsinger P, Tat V, Drelich A, Peng BH, Einav S, Tseng CK, Blish C, Lin MZ Sci Transl Med. 2024 Mar 13;16(738):eadi0979. doi: 10.1126/scitranslmed.adi0979. , Epub 2024 Mar 13. PMID:38478629<ref>PMID:38478629</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 7set" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 16:50, 18 October 2023

2023-10-18T16:50:15Z

← Older revision		Revision as of 16:50, 18 October 2023
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	~~'''Unreleased structure'''~~

	The ~~entry 7set~~ is ~~ON HOLD~~ ~~until Paper Publication~~		==SARS-CoV-2 Main Protease (Mpro) in Complex with ML1000==
			<StructureSection load='7set' size='340' side='right'caption='[[7set]], [[Resolution\|resolution]] 1.70Å' scene=''>
	~~Authors~~:		== Structural highlights ==
			<table><tr><td colspan='2'>[[7set]] 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=7SET OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SET FirstGlance]. <br>
	~~Description~~:		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.7Å</td></tr>
	[[Category: ~~Unreleased Structures~~]]		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=I70:(1R,2S,5S)-N-{(2S,3R)-4-amino-3-hydroxy-4-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-3-[N-(tert-butylcarbamoyl)-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide'>I70</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=7set FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7set OCA], [https://pdbe.org/7set PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7set RCSB], [https://www.ebi.ac.uk/pdbsum/7set PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7set 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]
			== References ==
			<references/>
			__TOC__
			</StructureSection>
			[[Category: Large Structures]]
			[[Category: Severe acute respiratory syndrome coronavirus 2]]
			[[Category: Fernandez D]]
			[[Category: Lin MZ]]
			[[Category: Westberg M]]

OCA at 15:06, 20 October 2021

2021-10-20T15:06:17Z

← Older revision		Revision as of 15:06, 20 October 2021
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 7set is ON HOLD		The entry 7set is ON HOLD until Paper Publication

	Authors:		Authors:

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

2021-10-13T10:25:17Z

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

← Older revision	Revision as of 10:25, 13 October 2021
(No difference)

OCA: New page: '''Unreleased structure''' The entry 7set is ON HOLD Authors: Description: Category: Unreleased Structures

2021-10-13T10:25:16Z

New page: '''Unreleased structure''' The entry 7set is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7set is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]