OCA at 18:05, 29 May 2024

OCA — Wed, 29 May 2024 18:05:04 GMT

←Older revision		Revision as of 18:05, 29 May 2024
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-	'''Unreleased structure'''

-	~~The entry~~ 8rjv is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalent inhibitor GUE-3778 (compound 12 in publication)==
		+	<StructureSection load='8rjv' size='340' side='right'caption='[[8rjv]], [[Resolution\|resolution]] 1.91Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8rjv]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus Severe acute respiratory syndrome coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8RJV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8RJV 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]] 1.91Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1H1J:(phenylmethyl)+~{N}-[(2~{S})-1-[[(3-chloranyl-2-fluoranyl-phenyl)methyl-(iminomethyl)amino]-methyl-amino]-1-oxidanylidene-3-phenyl-propan-2-yl]carbamate'>A1H1J</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=8rjv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8rjv OCA], [https://pdbe.org/8rjv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8rjv RCSB], [https://www.ebi.ac.uk/pdbsum/8rjv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8rjv 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 ==
		+	Given the crucial role of the main protease (M(pro)) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of M(pro). Our systematic approach combined an M(pro) active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent M(pro) inhibitor 84 with an IC(50) value of 3.23 nM and a second-order rate constant of inactivation, k(inac)/K(i), of 448,000 M(-1)s(-1). The open-chain M(pro) inhibitor 58, along with the macrocyclic compounds 83 and 84, a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC(50) values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic M(pro) inhibitors as anti-SARS-CoV-2 agents.

-	~~Authors~~: ~~Strater, N~~., ~~Claff~~, T., Sylvester, K., ~~Mueller~~, ~~C.E.~~, ~~Guetschow~~, M., ~~Useini~~, A.	+	Macrocyclic Azapeptide Nitriles: Structure-Based Discovery of Potent SARS-CoV-2 Main Protease Inhibitors as Antiviral Drugs.,Breidenbach J, Voget R, Si Y, Hingst A, Claff T, Sylvester K, Wolf V, Krasniqi V, Useini A, Strater N, Ogura Y, Kawaguchi A, Muller CE, Gutschow M J Med Chem. 2024 May 16. doi: 10.1021/acs.jmedchem.4c00053. PMID:38753594<ref>PMID:38753594</ref>

-	~~Description: Crystal structure~~ of ~~SARS-CoV-2 main protease (MPro) in complex with~~ the ~~covalent inhibitor GUE~~-~~3778 (compound 12 in publication)~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Sylvester, K~~]]	+	<div class="pdbe-citations 8rjv" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Useini, A~~]]	+	== References ==
-	[[Category: Guetschow, M]]	+	<references/>
-	[[Category: Mueller~~, C.E~~]]	+	__TOC__
-	[[Category: ~~Claff, T~~]]	+	</StructureSection>
-	[[Category: ~~Strater, N~~]]	+	[[Category: Large Structures]]
		+	[[Category: Severe acute respiratory syndrome coronavirus]]
		+	[[Category: Claff T]]
		+	[[Category: Guetschow M]]
		+	[[Category: Mueller CE]]
		+	[[Category: Strater N]]
		+	[[Category: Sylvester K]]
		+	[[Category: Useini A]]

OCA at 10:11, 24 January 2024

OCA — Wed, 24 Jan 2024 10:11:20 GMT

←Older revision		Revision as of 10:11, 24 January 2024
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Strater, N., Claff, T., Sylvester, K., Mueller, C.E., Guetschow, M., Useini, A.		Authors: Strater, N., Claff, T., Sylvester, K., Mueller, C.E., Guetschow, M., Useini, A.
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	Description: Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalent inhibitor GUE-3778 (compound 12 in publication)		Description: Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalent inhibitor GUE-3778 (compound 12 in publication)
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Guetschow, M]]
-	[[Category: Claff, T]]
	[[Category: Sylvester, K]]		[[Category: Sylvester, K]]
	[[Category: Useini, A]]		[[Category: Useini, A]]
		+	[[Category: Guetschow, M]]
	[[Category: Mueller, C.E]]		[[Category: Mueller, C.E]]
		+	[[Category: Claff, T]]
	[[Category: Strater, N]]		[[Category: Strater, N]]

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

OCA — Wed, 27 Dec 2023 22:10:53 GMT

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

←Older revision

Revision as of 22:10, 27 December 2023

OCA: New page: '''Unreleased structure''' The entry 8rjv is ON HOLD Authors: Strater, N., Claff, T., Sylvester, K., Mueller, C.E., Guetschow, M., Useini, A. Description: Crystal structure of SARS-CoV...

OCA — Wed, 27 Dec 2023 22:10:52 GMT

New page: '''Unreleased structure''' The entry 8rjv is ON HOLD Authors: Strater, N., Claff, T., Sylvester, K., Mueller, C.E., Guetschow, M., Useini, A. Description: Crystal structure of SARS-CoV...

New page

'''Unreleased structure'''

The entry 8rjv is ON HOLD

Authors: Strater, N., Claff, T., Sylvester, K., Mueller, C.E., Guetschow, M., Useini, A.

Description: Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalent inhibitor GUE-3778 (compound 12 in publication)
[[Category: Unreleased Structures]]
[[Category: Guetschow, M]]
[[Category: Claff, T]]
[[Category: Sylvester, K]]
[[Category: Useini, A]]
[[Category: Mueller, C.E]]
[[Category: Strater, N]]

8rjv - Revision history

OCA at 18:05, 29 May 2024

OCA at 10:11, 24 January 2024

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

OCA: New page: '''Unreleased structure''' The entry 8rjv is ON HOLD Authors: Strater, N., Claff, T., Sylvester, K., Mueller, C.E., Guetschow, M., Useini, A. Description: Crystal structure of SARS-CoV...