7ql8 - Revision history

OCA at 13:19, 1 February 2024

OCA — Thu, 01 Feb 2024 13:19:13 GMT

←Older revision		Revision as of 13:19, 1 February 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7ql8]] 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=7QL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QL8 FirstGlance]. <br>		<table><tr><td colspan='2'>[[7ql8]] 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=7QL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QL8 FirstGlance]. <br>
-	</td></tr><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>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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]] 1.807Å</td></tr>
		+	<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>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=7ql8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ql8 OCA], [https://pdbe.org/7ql8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ql8 RCSB], [https://www.ebi.ac.uk/pdbsum/7ql8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ql8 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=7ql8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ql8 OCA], [https://pdbe.org/7ql8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ql8 RCSB], [https://www.ebi.ac.uk/pdbsum/7ql8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ql8 ProSAT]</span></td></tr>
	</table>		</table>

OCA at 07:44, 9 November 2022

OCA — Wed, 09 Nov 2022 07:44:44 GMT

←Older revision		Revision as of 07:44, 9 November 2022
Line 1:		Line 1:

	==SARS-COV2 Main Protease in complex with inhibitor MG78==		==SARS-COV2 Main Protease in complex with inhibitor MG78==
-	<StructureSection load='7ql8' size='340' side='right'caption='[[7ql8]]' scene=''>	+	<StructureSection load='7ql8' size='340' side='right'caption='[[7ql8]], [[Resolution\|resolution]] 1.81Å' 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=7QL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QL8 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7ql8]] 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=7QL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QL8 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=7ql8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ql8 OCA], [https://pdbe.org/7ql8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ql8 RCSB], [https://www.ebi.ac.uk/pdbsum/7ql8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ql8 ProSAT]</span></td></tr>	+	</td></tr><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>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=7ql8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ql8 OCA], [https://pdbe.org/7ql8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ql8 RCSB], [https://www.ebi.ac.uk/pdbsum/7ql8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ql8 ProSAT]</span></td></tr>
	</table>		</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 ==
		+	The main protease (M(pro)) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the M(pro). Starting from crystal structures of the M(pro) in complexes with the Hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir, we optimized the potency of the alpha-ketoamide boceprevir against the M(pro) by replacing its P1 cyclobutyl moiety by a gamma-lactam as a glutamine surrogate. The resulting compound, MG-78, exhibited an IC50 of 13 nM versus the recombinant M(pro), and similar potency was observed for its P1' N-methyl derivative MG-131. Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 M(pro) inhibition, we also explored the activity of MG-78 against the M(pro) of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 microM, HCoV-NL63 M(pro)), moderate (1.45 microM, Coxsackievirus 3C(pro)), and relatively poor (6.7 microM, enterovirus A71 3C(pro)), respectively. The structural basis for the differences in activities was revealed by X-ray crystallo-graphy. We conclude that the modified boceprevir scaffold is suitable for obtaining high-potency inhibitors of the coronavirus M(pro)s but further optimization would be needed to target enterovirus 3C(pro)s efficiently.
		+
		+	From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease.,Gohl M, Zhang L, El Kilani H, Sun X, Zhang K, Bronstrup M, Hilgenfeld R Molecules. 2022 Jul 4;27(13). pii: molecules27134292. doi:, 10.3390/molecules27134292. PMID:35807537<ref>PMID:35807537</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7ql8" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
		+	[[Category: Severe acute respiratory syndrome coronavirus 2]]
	[[Category: El Kilani H]]		[[Category: El Kilani H]]
	[[Category: Hilgenfeld R]]		[[Category: Hilgenfeld R]]

OCA at 11:38, 27 April 2022

OCA — Wed, 27 Apr 2022 11:38:52 GMT

←Older revision		Revision as of 11:38, 27 April 2022
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-	'''Unreleased structure'''

-	~~The entry 7ql8 is ON HOLD~~	+	==SARS-COV2 Main Protease in complex with inhibitor MG78==
-		+	<StructureSection load='7ql8' size='340' side='right'caption='[[7ql8]]' scene=''>
-	~~Authors: El Kilani, H., Hilgenfeld, R.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QL8 FirstGlance]. <br>
-	~~Description:~~ SARS-COV2 Main Protease in complex with inhibitor MG78	+	</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=7ql8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ql8 OCA], [https://pdbe.org/7ql8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ql8 RCSB], [https://www.ebi.ac.uk/pdbsum/7ql8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ql8 ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Hilgenfeld~~, R]]	+	__TOC__
-	[[Category: El Kilani, H]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: El Kilani H]]
		+	[[Category: Hilgenfeld R]]

OCA at 04:57, 2 March 2022

OCA — Wed, 02 Mar 2022 04:57:17 GMT

←Older revision		Revision as of 04:57, 2 March 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7ql8 is ON HOLD ~~until sometime in the future~~	+	The entry 7ql8 is ON HOLD

	Authors: El Kilani, H., Hilgenfeld, R.		Authors: El Kilani, H., Hilgenfeld, R.

-	Description: Main Protease in complex with inhibitor MG78	+	Description: SARS-COV2 Main Protease in complex with inhibitor MG78
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Hilgenfeld, R]]		[[Category: Hilgenfeld, R]]
	[[Category: El Kilani, H]]		[[Category: El Kilani, H]]

OCA at 08:29, 12 January 2022

OCA — Wed, 12 Jan 2022 08:29:46 GMT

←Older revision		Revision as of 08:29, 12 January 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7ql8 is ON HOLD	+	The entry 7ql8 is ON HOLD until sometime in the future

	Authors: El Kilani, H., Hilgenfeld, R.		Authors: El Kilani, H., Hilgenfeld, R.

OCA: Protected "7ql8" [edit=sysop:move=sysop]

OCA — Wed, 29 Dec 2021 11:51:44 GMT

Protected "7ql8" [edit=sysop:move=sysop]

←Older revision

Revision as of 11:51, 29 December 2021

OCA: New page: '''Unreleased structure''' The entry 7ql8 is ON HOLD Authors: El Kilani, H., Hilgenfeld, R. Description: Main Protease in complex with inhibitor MG78 [[Category: Unreleased Structures]...

OCA — Wed, 29 Dec 2021 11:51:43 GMT

New page: '''Unreleased structure''' The entry 7ql8 is ON HOLD Authors: El Kilani, H., Hilgenfeld, R. Description: Main Protease in complex with inhibitor MG78 [[Category: Unreleased Structures]...

New page

'''Unreleased structure'''

The entry 7ql8 is ON HOLD

Authors: El Kilani, H., Hilgenfeld, R.

Description: Main Protease in complex with inhibitor MG78
[[Category: Unreleased Structures]]
[[Category: Hilgenfeld, R]]
[[Category: El Kilani, H]]