7vlq - Revision history

OCA at 17:27, 29 November 2023

OCA — Wed, 29 Nov 2023 17:27:55 GMT

←Older revision		Revision as of 17:27, 29 November 2023
Line 1:		Line 1:

	==Crystal structure of SARS-Cov-2 main protease in complex with PF07321332 in spacegroup P212121==		==Crystal structure of SARS-Cov-2 main protease in complex with PF07321332 in spacegroup P212121==
-	<StructureSection load='7vlq' size='340' side='right'caption='[[7vlq]]' scene=''>	+	<StructureSection load='7vlq' size='340' side='right'caption='[[7vlq]], [[Resolution\|resolution]] 1.94Å' 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=7VLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VLQ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7vlq]] 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=7VLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VLQ 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=7vlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vlq OCA], [https://pdbe.org/7vlq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vlq RCSB], [https://www.ebi.ac.uk/pdbsum/7vlq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vlq 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]] 1.939106Å</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=7vlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vlq OCA], [https://pdbe.org/7vlq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vlq RCSB], [https://www.ebi.ac.uk/pdbsum/7vlq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vlq 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 ==
		+	The high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genera of coronaviruses is the substrate-binding site of the main protease (M(pro) or 3CL(pro)), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332, developed by Pfizer, is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here, we report three crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome (MERS)-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of the main protease harbors multiple inhibitor-binding sites, where PF-07321332 occupies subsites S1, S2, and S4 and appears more restricted than other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of the main proteases from different coronaviruses. Given the importance of the main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals. IMPORTANCE The current pandemic of multiple variants has created an urgent need for effective inhibitors of SARS-CoV-2 to complement vaccine strategies. PF-07321332, developed by Pfizer, is the first orally administered coronavirus-specific main protease inhibitor approved by the FDA. We solved the crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and MERS-CoV that bound to the PF-07321332, suggesting PF-07321332 is a broad-spectrum inhibitor for coronaviruses. Structures of the main protease inhibitor complexes present an opportunity to discover safer and more effective inhibitors for COVID-19.
		+
		+	Structural Basis of the Main Proteases of Coronavirus Bound to Drug Candidate PF-07321332.,Li J, Lin C, Zhou X, Zhong F, Zeng P, Yang Y, Zhang Y, Yu B, Fan X, McCormick PJ, Fu R, Fu Y, Jiang H, Zhang J J Virol. 2022 Apr 27;96(8):e0201321. doi: 10.1128/jvi.02013-21. Epub 2022 Apr 7. PMID:35389231<ref>PMID:35389231</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7vlq" 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: Li J]]		[[Category: Li J]]
	[[Category: Lin C]]		[[Category: Lin C]]

OCA at 11:12, 31 August 2022

OCA — Wed, 31 Aug 2022 11:12:17 GMT

←Older revision		Revision as of 11:12, 31 August 2022
Line 1:		Line 1:

	==Crystal structure of SARS-Cov-2 main protease in complex with PF07321332 in spacegroup P212121==		==Crystal structure of SARS-Cov-2 main protease in complex with PF07321332 in spacegroup P212121==
-	<StructureSection load='7vlq' size='340' side='right'caption='[[7vlq]]~~, [[Resolution\|resolution]] 1.94Å~~' scene=''>	+	<StructureSection load='7vlq' size='340' side='right'caption='[[7vlq]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>~~[[7vlq]] is a 2 chain structure.~~ Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VLQ FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VLQ FirstGlance]. <br>
-	</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>	+	</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=7vlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vlq OCA], [https://pdbe.org/7vlq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vlq RCSB], [https://www.ebi.ac.uk/pdbsum/7vlq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vlq ProSAT]</span></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/SARS_coronavirus_main_proteinase SARS coronavirus main proteinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.69 3.4.22.69] </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=7vlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vlq OCA], [https://pdbe.org/7vlq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vlq RCSB], [https://www.ebi.ac.uk/pdbsum/7vlq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vlq 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 high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genera of coronaviruses is the substrate-binding site of the main protease (M(pro) or 3CL(pro)), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332, developed by Pfizer, is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here, we report three crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome (MERS)-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of the main protease harbors multiple inhibitor-binding sites, where PF-07321332 occupies subsites S1, S2, and S4 and appears more restricted than other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of the main proteases from different coronaviruses. Given the importance of the main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals. IMPORTANCE The current pandemic of multiple variants has created an urgent need for effective inhibitors of SARS-CoV-2 to complement vaccine strategies. PF-07321332, developed by Pfizer, is the first orally administered coronavirus-specific main protease inhibitor approved by the FDA. We solved the crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and MERS-CoV that bound to the PF-07321332, suggesting PF-07321332 is a broad-spectrum inhibitor for coronaviruses. Structures of the main protease inhibitor complexes present an opportunity to discover safer and more effective inhibitors for COVID-19.
-
-	Structural Basis of the Main Proteases of Coronavirus Bound to Drug Candidate PF-07321332.,Li J, Lin C, Zhou X, Zhong F, Zeng P, Yang Y, Zhang Y, Yu B, Fan X, McCormick PJ, Fu R, Fu Y, Jiang H, Zhang J J Virol. 2022 Apr 27;96(8):e0201321. doi: 10.1128/jvi.02013-21. Epub 2022 Apr 7. PMID:35389231<ref>PMID:35389231</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 7vlq" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: SARS coronavirus main proteinase]]~~	+	[[Category: Li J]]
-	[[Category: Li, J]]	+	[[Category: Lin C]]
-	[[Category: Lin, C]]	+	[[Category: Zhang J]]
-	[[Category: Zhang, J]]	+	[[Category: Zhong FL]]
-	[[Category: Zhong~~, F L~~]]	+	[[Category: Zhou XL]]
-	[[Category: Zhou~~, X L]]~~	+
-	~~[[Category: Viral protein-inhibitor complex~~]]	+

OCA at 05:15, 25 August 2022

OCA — Thu, 25 Aug 2022 05:15:48 GMT

←Older revision		Revision as of 05:15, 25 August 2022
Line 1:		Line 1:

	==Crystal structure of SARS-Cov-2 main protease in complex with PF07321332 in spacegroup P212121==		==Crystal structure of SARS-Cov-2 main protease in complex with PF07321332 in spacegroup P212121==
-	<StructureSection load='7vlq' size='340' side='right'caption='[[7vlq]]' scene=''>	+	<StructureSection load='7vlq' size='340' side='right'caption='[[7vlq]], [[Resolution\|resolution]] 1.94Å' 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=7VLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VLQ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7vlq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VLQ 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=7vlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vlq OCA], [https://pdbe.org/7vlq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vlq RCSB], [https://www.ebi.ac.uk/pdbsum/7vlq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vlq 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=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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/SARS_coronavirus_main_proteinase SARS coronavirus main proteinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.69 3.4.22.69] </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=7vlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vlq OCA], [https://pdbe.org/7vlq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vlq RCSB], [https://www.ebi.ac.uk/pdbsum/7vlq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vlq 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 high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genera of coronaviruses is the substrate-binding site of the main protease (M(pro) or 3CL(pro)), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332, developed by Pfizer, is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here, we report three crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome (MERS)-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of the main protease harbors multiple inhibitor-binding sites, where PF-07321332 occupies subsites S1, S2, and S4 and appears more restricted than other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of the main proteases from different coronaviruses. Given the importance of the main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals. IMPORTANCE The current pandemic of multiple variants has created an urgent need for effective inhibitors of SARS-CoV-2 to complement vaccine strategies. PF-07321332, developed by Pfizer, is the first orally administered coronavirus-specific main protease inhibitor approved by the FDA. We solved the crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and MERS-CoV that bound to the PF-07321332, suggesting PF-07321332 is a broad-spectrum inhibitor for coronaviruses. Structures of the main protease inhibitor complexes present an opportunity to discover safer and more effective inhibitors for COVID-19.
		+
		+	Structural Basis of the Main Proteases of Coronavirus Bound to Drug Candidate PF-07321332.,Li J, Lin C, Zhou X, Zhong F, Zeng P, Yang Y, Zhang Y, Yu B, Fan X, McCormick PJ, Fu R, Fu Y, Jiang H, Zhang J J Virol. 2022 Apr 27;96(8):e0201321. doi: 10.1128/jvi.02013-21. Epub 2022 Apr 7. PMID:35389231<ref>PMID:35389231</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7vlq" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Li J]]	+	[[Category: SARS coronavirus main proteinase]]
-	[[Category: Lin C]]	+	[[Category: Li, J]]
-	[[Category: Zhang J]]	+	[[Category: Lin, C]]
-	[[Category: Zhong FL]]	+	[[Category: Zhang, J]]
-	[[Category: Zhou XL]]	+	[[Category: Zhong, F L]]
		+	[[Category: Zhou, X L]]
		+	[[Category: Viral protein-inhibitor complex]]

OCA at 10:27, 6 April 2022

OCA — Wed, 06 Apr 2022 10:27:34 GMT

←Older revision		Revision as of 10:27, 6 April 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7vlq ~~is ON HOLD until Oct 05 2023~~	+	==Crystal structure of SARS-Cov-2 main protease in complex with PF07321332 in spacegroup P212121==
-		+	<StructureSection load='7vlq' size='340' side='right'caption='[[7vlq]]' scene=''>
-	~~Authors~~: ~~Zhou, X~~.L., ~~Zhong, F~~.L., ~~Lin, C~~., ~~Zhang, J~~., Li, J.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VLQ FirstGlance]. <br>
-	~~Description: Crystal structure of SARS-Cov-2 main protease in complex with PF07321332 in spacegroup P212121~~	+	</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=7vlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vlq OCA], [https://pdbe.org/7vlq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vlq RCSB], [https://www.ebi.ac.uk/pdbsum/7vlq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vlq ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Lin, C~~]]	+	__TOC__
-	[[Category: ~~Li, J~~]]	+	</StructureSection>
-	[[Category: ~~Zhong, F.L~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Zhou, X.L~~]]	+	[[Category: Li J]]
-	[[Category: ~~Zhang, J~~]]	+	[[Category: Lin C]]
		+	[[Category: Zhang J]]
		+	[[Category: Zhong FL]]
		+	[[Category: Zhou XL]]

OCA at 12:18, 17 November 2021

OCA — Wed, 17 Nov 2021 12:18:19 GMT

←Older revision		Revision as of 12:18, 17 November 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7vlq is ON HOLD	+	The entry 7vlq is ON HOLD until Oct 05 2023

	Authors: Zhou, X.L., Zhong, F.L., Lin, C., Zhang, J., Li, J.		Authors: Zhou, X.L., Zhong, F.L., Lin, C., Zhang, J., Li, J.

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

OCA — Wed, 13 Oct 2021 10:34:26 GMT

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

←Older revision

Revision as of 10:34, 13 October 2021

OCA: New page: '''Unreleased structure''' The entry 7vlq is ON HOLD Authors: Zhou, X.L., Zhong, F.L., Lin, C., Zhang, J., Li, J. Description: Crystal structure of SARS-Cov-2 main protease in complex ...

OCA — Wed, 13 Oct 2021 10:34:25 GMT

New page: '''Unreleased structure''' The entry 7vlq is ON HOLD Authors: Zhou, X.L., Zhong, F.L., Lin, C., Zhang, J., Li, J. Description: Crystal structure of SARS-Cov-2 main protease in complex ...

New page

'''Unreleased structure'''

The entry 7vlq is ON HOLD

Authors: Zhou, X.L., Zhong, F.L., Lin, C., Zhang, J., Li, J.

Description: Crystal structure of SARS-Cov-2 main protease in complex with PF07321332 in spacegroup P212121
[[Category: Unreleased Structures]]
[[Category: Lin, C]]
[[Category: Li, J]]
[[Category: Zhong, F.L]]
[[Category: Zhou, X.L]]
[[Category: Zhang, J]]