7tiw - Revision history

OCA at 17:04, 18 October 2023

OCA — Wed, 18 Oct 2023 17:04:51 GMT

←Older revision		Revision as of 17:04, 18 October 2023
Line 1:		Line 1:

	==Crystal structure of SARS-CoV-2 3CL in complex with inhibitor EB54==		==Crystal structure of SARS-CoV-2 3CL in complex with inhibitor EB54==
-	<StructureSection load='7tiw' size='340' side='right'caption='[[7tiw]]' scene=''>	+	<StructureSection load='7tiw' size='340' side='right'caption='[[7tiw]], [[Resolution\|resolution]] 1.68Å' 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=7TIW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TIW FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7tiw]] 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=7TIW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TIW 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=7tiw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tiw OCA], [https://pdbe.org/7tiw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tiw RCSB], [https://www.ebi.ac.uk/pdbsum/7tiw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tiw 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]] 1.68Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I54:(1S,2S)-2-[(N-{[(2-chlorophenyl)methoxy]carbonyl}-L-leucyl)amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic+acid'>I54</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7tiw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tiw OCA], [https://pdbe.org/7tiw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tiw RCSB], [https://www.ebi.ac.uk/pdbsum/7tiw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tiw 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 SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.
		+
		+	Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19.,Liu H, Iketani S, Zask A, Khanizeman N, Bednarova E, Forouhar F, Fowler B, Hong SJ, Mohri H, Nair MS, Huang Y, Tay NES, Lee S, Karan C, Resnick SJ, Quinn C, Li W, Shion H, Xia X, Daniels JD, Bartolo-Cruz M, Farina M, Rajbhandari P, Jurtschenko C, Lauber MA, McDonald T, Stokes ME, Hurst BL, Rovis T, Chavez A, Ho DD, Stockwell BR Nat Commun. 2022 Apr 7;13(1):1891. doi: 10.1038/s41467-022-29413-2. PMID:35393402<ref>PMID:35393402</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7tiw" 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: Bednarova E]]		[[Category: Bednarova E]]
	[[Category: Chavez A]]		[[Category: Chavez A]]

OCA at 12:52, 4 May 2022

OCA — Wed, 04 May 2022 12:52:00 GMT

←Older revision		Revision as of 12:52, 4 May 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7tiw ~~is ON HOLD until Paper Publication~~	+	==Crystal structure of SARS-CoV-2 3CL in complex with inhibitor EB54==
-		+	<StructureSection load='7tiw' size='340' side='right'caption='[[7tiw]]' scene=''>
-	~~Authors~~: ~~Forouhar, F~~.~~, Liu, H~~.~~, Iketani, S~~.~~, Zack, A~~.~~, Khanizeman, N~~.~~, Bednarova, E~~.~~, Fowler, B~~.~~, Hong, S~~.J., ~~Mohri, H~~.~~, Nair, M~~.S., ~~Huang, Y~~., ~~Tay, N~~.E.S., ~~Lee, S~~.~~, Karan, C~~.~~, Resnick, S.J~~., ~~Quinn, C~~.~~, Li, W., Shion, H., Jurtschenko, C., Lauber, M.A., McDonald, T., Stokes, M.E., Hurst, B., Rovis, T., Chavez, A., Ho, D.D., Stockwell, B.R~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TIW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TIW FirstGlance]. <br>
-	~~Description: Crystal structure of SARS-CoV-2 3CL in complex with inhibitor EB54~~	+	</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=7tiw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tiw OCA], [https://pdbe.org/7tiw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tiw RCSB], [https://www.ebi.ac.uk/pdbsum/7tiw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tiw ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Nair, M.S~~]]	+	__TOC__
-	[[Category: ~~Jurtschenko, C~~]]	+	</StructureSection>
-	[[Category: Forouhar, F]]	+	[[Category: Large Structures]]
-	[[Category: ~~Hurst,~~ B]]	+	[[Category: Bednarova E]]
-	[[Category: ~~Shion, H~~]]	+	[[Category: Chavez A]]
-	[[Category: ~~Iketani, S~~]]	+	[[Category: Forouhar F]]
-	[[Category: ~~Quinn, C~~]]	+	[[Category: Fowler B]]
-	[[Category: ~~Chavez, A~~]]	+	[[Category: Ho DD]]
-	[[Category: ~~Karan, C~~]]	+	[[Category: Hong SJ]]
-	[[Category: ~~Mohri, H~~]]	+	[[Category: Huang Y]]
-	[[Category: ~~Fowler, B~~]]	+	[[Category: Hurst B]]
-	[[Category: ~~Bednarova, E~~]]	+	[[Category: Iketani S]]
-	[[Category: ~~Li, W~~]]	+	[[Category: Jurtschenko C]]
-	[[Category: ~~Rovis, T~~]]	+	[[Category: Karan C]]
-	[[Category: ~~Huang, Y~~]]	+	[[Category: Khanizeman N]]
-	[[Category: ~~Lauber, M.A~~]]	+	[[Category: Lauber MA]]
-	[[Category: ~~Resnick, S.J~~]]	+	[[Category: Lee S]]
-	[[Category: ~~Stokes, M.E~~]]	+	[[Category: Li W]]
-	[[Category: ~~Ho, D.D~~]]	+	[[Category: Liu H]]
-	[[Category: ~~Hong, S.J~~]]	+	[[Category: McDonald T]]
-	[[Category: ~~Liu, H~~]]	+	[[Category: Mohri H]]
-	[[Category: ~~Lee, S~~]]	+	[[Category: Nair MS]]
-	[[Category: ~~Tay, N.E.S~~]]	+	[[Category: Quinn C]]
-	[[Category: ~~Khanizeman, N~~]]	+	[[Category: Resnick SJ]]
-	[[Category: ~~Stockwell, B.R~~]]	+	[[Category: Rovis T]]
-	[[Category: ~~Mcdonald, T~~]]	+	[[Category: Shion H]]
-	[[Category: Zack, A]]	+	[[Category: Stockwell BR]]
		+	[[Category: Stokes ME]]
		+	[[Category: Tay NES]]
		+	[[Category: Zack A]]

OCA at 06:29, 23 February 2022

OCA — Wed, 23 Feb 2022 06:29:27 GMT

←Older revision		Revision as of 06:29, 23 February 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Forouhar, F., Liu, H., Iketani, S., Zack, A., Khanizeman, N., Bednarova, E., Fowler, B., Hong, S.J., Mohri, H., Nair, M.S., Huang, Y., Tay, N.E.S., Lee, S., Karan, C., Resnick, S.J., Quinn, C., Li, W., Shion, H., Jurtschenko, C., Lauber, M.A., McDonald, T., Stokes, M.E., Hurst, B., Rovis, T., Chavez, A., Ho, D.D., Stockwell, B.R.		Authors: Forouhar, F., Liu, H., Iketani, S., Zack, A., Khanizeman, N., Bednarova, E., Fowler, B., Hong, S.J., Mohri, H., Nair, M.S., Huang, Y., Tay, N.E.S., Lee, S., Karan, C., Resnick, S.J., Quinn, C., Li, W., Shion, H., Jurtschenko, C., Lauber, M.A., McDonald, T., Stokes, M.E., Hurst, B., Rovis, T., Chavez, A., Ho, D.D., Stockwell, B.R.

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

OCA — Thu, 27 Jan 2022 05:29:41 GMT

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

←Older revision

Revision as of 05:29, 27 January 2022

OCA: New page: '''Unreleased structure''' The entry 7tiw is ON HOLD Authors: Forouhar, F., Liu, H., Iketani, S., Zack, A., Khanizeman, N., Bednarova, E., Fowler, B., Hong, S.J., Mohri, H., Nair, M.S.,...

OCA — Thu, 27 Jan 2022 05:29:39 GMT

New page: '''Unreleased structure''' The entry 7tiw is ON HOLD Authors: Forouhar, F., Liu, H., Iketani, S., Zack, A., Khanizeman, N., Bednarova, E., Fowler, B., Hong, S.J., Mohri, H., Nair, M.S.,...

New page

'''Unreleased structure'''

The entry 7tiw is ON HOLD

Authors: Forouhar, F., Liu, H., Iketani, S., Zack, A., Khanizeman, N., Bednarova, E., Fowler, B., Hong, S.J., Mohri, H., Nair, M.S., Huang, Y., Tay, N.E.S., Lee, S., Karan, C., Resnick, S.J., Quinn, C., Li, W., Shion, H., Jurtschenko, C., Lauber, M.A., McDonald, T., Stokes, M.E., Hurst, B., Rovis, T., Chavez, A., Ho, D.D., Stockwell, B.R.

Description: Crystal structure of SARS-CoV-2 3CL in complex with inhibitor EB54
[[Category: Unreleased Structures]]
[[Category: Nair, M.S]]
[[Category: Jurtschenko, C]]
[[Category: Forouhar, F]]
[[Category: Hurst, B]]
[[Category: Shion, H]]
[[Category: Iketani, S]]
[[Category: Quinn, C]]
[[Category: Chavez, A]]
[[Category: Karan, C]]
[[Category: Mohri, H]]
[[Category: Fowler, B]]
[[Category: Bednarova, E]]
[[Category: Li, W]]
[[Category: Rovis, T]]
[[Category: Huang, Y]]
[[Category: Lauber, M.A]]
[[Category: Resnick, S.J]]
[[Category: Stokes, M.E]]
[[Category: Ho, D.D]]
[[Category: Hong, S.J]]
[[Category: Liu, H]]
[[Category: Lee, S]]
[[Category: Tay, N.E.S]]
[[Category: Khanizeman, N]]
[[Category: Stockwell, B.R]]
[[Category: Mcdonald, T]]
[[Category: Zack, A]]