7p35 - Revision history

OCA at 07:52, 1 May 2024

2024-05-01T07:52:04Z

←Older revision		Revision as of 07:52, 1 May 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7p35]] 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=7P35 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P35 FirstGlance]. <br>		<table><tr><td colspan='2'>[[7p35]] 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=7P35 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P35 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AG7:4-{2-(4-FLUORO-BENZYL)-6-METHYL-5-[(5-METHYL-ISOXAZOLE-3-CARBONYL)-AMINO]-4-OXO-HEPTANOYLAMINO}-5-(2-OXO-PYRROLIDIN-3-YL)-PENTANOIC+ACID+ETHYL+ESTER'>AG7</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]] 2.256Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AG7:4-{2-(4-FLUORO-BENZYL)-6-METHYL-5-[(5-METHYL-ISOXAZOLE-3-CARBONYL)-AMINO]-4-OXO-HEPTANOYLAMINO}-5-(2-OXO-PYRROLIDIN-3-YL)-PENTANOIC+ACID+ETHYL+ESTER'>AG7</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=7p35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p35 OCA], [https://pdbe.org/7p35 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p35 RCSB], [https://www.ebi.ac.uk/pdbsum/7p35 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p35 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=7p35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p35 OCA], [https://pdbe.org/7p35 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p35 RCSB], [https://www.ebi.ac.uk/pdbsum/7p35 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p35 ProSAT]</span></td></tr>
	</table>		</table>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) pose a threat to global public health. The 3C-like main protease (M(pro)), which presents structural similarity with the active site domain of enterovirus 3C protease, is one of the best-characterized drug targets of these viruses. Here we studied the antiviral activity of the orally bioavailable enterovirus protease inhibitor AG7404 against SARS-CoV-1 and SARS-CoV-2 from a structural, biochemical, and cellular perspective, comparing it with the related molecule rupintrivir (AG7800). Crystallographic structures of AG7404 in complex with SARS-CoV-1 M(pro) and SARS-CoV-2 M(pro) and of rupintrivir in complex with SARS-CoV-2 M(pro) were solved, revealing that all protein residues interacting with the inhibitors are conserved between the two proteins. A detailed analysis of protein-inhibitor interactions indicates that AG7404 has a better fit to the active site of the target protease than rupintrivir. This observation was further confirmed by biochemical FRET assays showing IC(50) values of 47 muM and 101 muM for AG7404 and rupintrivir, respectively, in the case of SARS-CoV-2 M(pro). Equivalent IC(50) values for SARS-CoV-1 also revealed greater inhibitory capacity of AG7404, with a value of 29 muM vs. 66 muM for rupintrivir. Finally, the antiviral activity of the two inhibitors against SARS-CoV-2 was confirmed in a human cell culture model of SARS-CoV-2 infection, although rupintrivir showed a higher potency and selectivity index in this assay.

-	Structure and inhibition of SARS-CoV-1 and SARS-CoV-2 main proteases by oral antiviral compound AG7404.,Fabrega-Ferrer M, Herrera-Morande A, Muriel-Goni S, Perez-Saavedra J, Bueno P, Castro V, Garaigorta U, Gastaminza P, Coll M Antiviral Res. 2022 Dec;208:105458. doi: 10.1016/j.antiviral.2022.105458. Epub , 2022 Nov 3. PMID:36336176<ref>PMID:36336176</ref>	+	==See Also==
-		+	*[[RNA polymerase 3D structures\|RNA polymerase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 7p35" style="background-color:#fffaf0;"></div>~~	+
-	== ~~References~~ ==	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 09:13, 28 December 2022

2022-12-28T09:13:33Z

←Older revision		Revision as of 09:13, 28 December 2022
Line 1:		Line 1:

	==Structure of the SARS-CoV-2 3CL protease in complex with rupintrivir==		==Structure of the SARS-CoV-2 3CL protease in complex with rupintrivir==
-	<StructureSection load='7p35' size='340' side='right'caption='[[7p35]]' scene=''>	+	<StructureSection load='7p35' size='340' side='right'caption='[[7p35]], [[Resolution\|resolution]] 2.26Å' 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=7P35 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P35 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7p35]] 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=7P35 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P35 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=7p35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p35 OCA], [https://pdbe.org/7p35 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p35 RCSB], [https://www.ebi.ac.uk/pdbsum/7p35 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p35 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=AG7:4-{2-(4-FLUORO-BENZYL)-6-METHYL-5-[(5-METHYL-ISOXAZOLE-3-CARBONYL)-AMINO]-4-OXO-HEPTANOYLAMINO}-5-(2-OXO-PYRROLIDIN-3-YL)-PENTANOIC+ACID+ETHYL+ESTER'>AG7</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=7p35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p35 OCA], [https://pdbe.org/7p35 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p35 RCSB], [https://www.ebi.ac.uk/pdbsum/7p35 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p35 ProSAT]</span></td></tr>
	</table>		</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) pose a threat to global public health. The 3C-like main protease (M(pro)), which presents structural similarity with the active site domain of enterovirus 3C protease, is one of the best-characterized drug targets of these viruses. Here we studied the antiviral activity of the orally bioavailable enterovirus protease inhibitor AG7404 against SARS-CoV-1 and SARS-CoV-2 from a structural, biochemical, and cellular perspective, comparing it with the related molecule rupintrivir (AG7800). Crystallographic structures of AG7404 in complex with SARS-CoV-1 M(pro) and SARS-CoV-2 M(pro) and of rupintrivir in complex with SARS-CoV-2 M(pro) were solved, revealing that all protein residues interacting with the inhibitors are conserved between the two proteins. A detailed analysis of protein-inhibitor interactions indicates that AG7404 has a better fit to the active site of the target protease than rupintrivir. This observation was further confirmed by biochemical FRET assays showing IC(50) values of 47 muM and 101 muM for AG7404 and rupintrivir, respectively, in the case of SARS-CoV-2 M(pro). Equivalent IC(50) values for SARS-CoV-1 also revealed greater inhibitory capacity of AG7404, with a value of 29 muM vs. 66 muM for rupintrivir. Finally, the antiviral activity of the two inhibitors against SARS-CoV-2 was confirmed in a human cell culture model of SARS-CoV-2 infection, although rupintrivir showed a higher potency and selectivity index in this assay.
		+
		+	Structure and inhibition of SARS-CoV-1 and SARS-CoV-2 main proteases by oral antiviral compound AG7404.,Fabrega-Ferrer M, Herrera-Morande A, Muriel-Goni S, Perez-Saavedra J, Bueno P, Castro V, Garaigorta U, Gastaminza P, Coll M Antiviral Res. 2022 Dec;208:105458. doi: 10.1016/j.antiviral.2022.105458. Epub , 2022 Nov 3. PMID:36336176<ref>PMID:36336176</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7p35" 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: Coll M]]		[[Category: Coll M]]
	[[Category: Fabrega-Ferrer M]]		[[Category: Fabrega-Ferrer M]]
	[[Category: Herrera-Morande A]]		[[Category: Herrera-Morande A]]
	[[Category: Perez-Saavedra J]]		[[Category: Perez-Saavedra J]]

OCA at 09:00, 21 July 2021

2021-07-21T09:00:18Z

←Older revision		Revision as of 09:00, 21 July 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7p35 ~~is ON HOLD~~	+	==Structure of the SARS-CoV-2 3CL protease in complex with rupintrivir==
-		+	<StructureSection load='7p35' size='340' side='right'caption='[[7p35]]' scene=''>
-	~~Authors~~: ~~Fabrega~~-~~Ferrer, M~~., ~~Perez~~-~~Saavedra~~, J., ~~Herrera-Morande~~, A., ~~Coll, M~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7P35 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P35 FirstGlance]. <br>
-	~~Description: Structure of the SARS-CoV-2 3CL protease in complex with rupintrivir~~	+	</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=7p35 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p35 OCA], [https://pdbe.org/7p35 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p35 RCSB], [https://www.ebi.ac.uk/pdbsum/7p35 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p35 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Herrera-Morande, A~~]]	+	__TOC__
-	[[Category: ~~Coll,~~ M]]	+	</StructureSection>
-	[[Category: ~~Perez~~-~~Saavedra, J~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Fabrega~~-~~Ferrer, M~~]]	+	[[Category: Coll M]]
		+	[[Category: Fabrega-Ferrer M]]
		+	[[Category: Herrera-Morande A]]
		+	[[Category: Perez-Saavedra J]]

OCA: Protected "7p35" [edit=sysop:move=sysop]

2021-07-14T08:52:51Z

Protected "7p35" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:52, 14 July 2021

OCA: New page: '''Unreleased structure''' The entry 7p35 is ON HOLD Authors: Fabrega-Ferrer, M., Perez-Saavedra, J., Herrera-Morande, A., Coll, M. Description: Structure of the SARS-CoV-2 3CL proteas...

2021-07-14T08:52:50Z

New page: '''Unreleased structure''' The entry 7p35 is ON HOLD Authors: Fabrega-Ferrer, M., Perez-Saavedra, J., Herrera-Morande, A., Coll, M. Description: Structure of the SARS-CoV-2 3CL proteas...

New page

'''Unreleased structure'''

The entry 7p35 is ON HOLD

Authors: Fabrega-Ferrer, M., Perez-Saavedra, J., Herrera-Morande, A., Coll, M.

Description: Structure of the SARS-CoV-2 3CL protease in complex with rupintrivir
[[Category: Unreleased Structures]]
[[Category: Herrera-Morande, A]]
[[Category: Coll, M]]
[[Category: Perez-Saavedra, J]]
[[Category: Fabrega-Ferrer, M]]