OCA at 08:24, 11 October 2023

OCA — Wed, 11 Oct 2023 08:24:24 GMT

←Older revision		Revision as of 08:24, 11 October 2023
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	==Co-crystal structures of CHIKV nsP3 macrodomain with pyrimidone fragments==		==Co-crystal structures of CHIKV nsP3 macrodomain with pyrimidone fragments==
-	<StructureSection load='6w0t' size='340' side='right'caption='[[6w0t]]' scene=''>	+	<StructureSection load='6w0t' size='340' side='right'caption='[[6w0t]], [[Resolution\|resolution]] 1.95Å' 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=6W0T OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6W0T FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6w0t]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Chikungunya_virus_strain_Senegal_37997 Chikungunya virus strain Senegal 37997]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W0T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W0T FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=6w0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w0t OCA], [~~http~~://pdbe.org/6w0t PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6w0t RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6w0t PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6w0t 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]] 1.95Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S6Y:6-(2-methylpropyl)-2-oxidanylidene-5~{H}-pyrimidine-4-carboxylic+acid'>S6Y</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=6w0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w0t OCA], [https://pdbe.org/6w0t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w0t RCSB], [https://www.ebi.ac.uk/pdbsum/6w0t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w0t ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/POLN_CHIKS POLN_CHIKS] P123 is short-lived polyproteins, accumulating during early stage of infection. It localizes the viral replication complex to the cytoplasmic surface of modified endosomes and lysosomes. By interacting with nsP4, it starts viral genome replication into antigenome. After these early events, P123 is cleaved sequentially into nsP1, nsP2 and nsP3. This sequence of delayed processing would allow correct assembly and membrane association of the RNA polymerase complex (By similarity). nsP1 is a cytoplasmic capping enzyme. This function is necessary since all viral RNAs are synthesized in the cytoplasm, and host capping enzymes are restricted to the nucleus. The enzymatic reaction involves a covalent link between 7-methyl-GMP and nsP1, whereas eukaryotic capping enzymes form a covalent complex only with GMP. nsP1 capping would consist in the following reactions: GTP is first methylated and then forms the m7GMp-nsP1 complex, from which 7-methyl-GMP complex is transferred to the mRNA to create the cap structure. Palmitoylated nsP1 is remodeling host cell cytoskeleton, and induces filopodium-like structure formation at the surface of the host cell (By similarity). nsP2 has two separate domain with different biological activities. The N-terminal section is part of the RNA polymerase complex and has RNA trisphosphatase and RNA helicase activity. The C-terminal section harbors a protease that specifically cleaves and releases the four mature proteins (By similarity). Also inhibits cellular transcription by inducing rapid degradation of POLR2A, a catalytic subunit of the RNAPII complex. The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response. nsP3 is essential for minus strand and subgenomic 26S mRNA synthesis (By similarity). nsP4 is an RNA dependent RNA polymerase. It replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a 26S subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This 26S mRNA codes for structural proteins (By similarity).
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The macrodomain of nsP3 (nsP3MD) is highly conserved among the alphaviruses and ADP-ribosylhydrolase activity of Chikungunya Virus (CHIKV) nsP3MD is critical for CHIKV viral replication and virulence. No small molecule drugs targeting CHIKV nsP3 have been identified to date. Here we report small fragments that bind to nsP3MD which were discovered by virtually screening a fragment library and X-ray crystallography. These identified fragments share a similar scaffold, 2-pyrimidone-4-carboxylic acid, and are specifically bound to the ADP-ribose binding site of nsP3MD. Among the fragments, 2-oxo-5,6-benzopyrimidine-4-carboxylic acid showed anti-CHIKV activity with an IC50 of 23 muM. Our fragment-based drug discovery approach provides valuable information to further develop a specific and potent nsP3 inhibitor of CHIKV viral replication based on the 2-pyrimidone-4-carboxylic acid scaffold. In silico studies suggest this pyrimidone scaffold could also bind to the macrodomains of other alphaviruses and coronaviruses and thus, have potential pan-antiviral activity.
		+
		+	Pyrimidone inhibitors targeting Chikungunya Virus nsP3 macrodomain by fragment-based drug design.,Zhang S, Garzan A, Haese N, Bostwick R, Martinez-Gzegozewska Y, Rasmussen L, Streblow DN, Haise MT, Pathak AK, Augelli-Szafran CE, Wu M PLoS One. 2021 Jan 22;16(1):e0245013. doi: 10.1371/journal.pone.0245013. , eCollection 2021. PMID:33482665<ref>PMID:33482665</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6w0t" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Chikungunya virus strain Senegal 37997]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Wu M]]		[[Category: Wu M]]
	[[Category: Zhang S]]		[[Category: Zhang S]]

OCA at 05:49, 20 January 2021

OCA — Wed, 20 Jan 2021 05:49:26 GMT

←Older revision		Revision as of 05:49, 20 January 2021
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-	'''Unreleased structure'''

-	~~The entry 6w0t is ON HOLD until Paper Publication~~	+	==Co-crystal structures of CHIKV nsP3 macrodomain with pyrimidone fragments==
-		+	<StructureSection load='6w0t' size='340' side='right'caption='[[6w0t]]' scene=''>
-	~~Authors: Wu, M., Zhang, S.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W0T OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W0T FirstGlance]. <br>
-	~~Description:~~ Co-crystal structures of CHIKV nsP3 macrodomain with pyrimidone fragments	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w0t OCA], [http://pdbe.org/6w0t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w0t RCSB], [http://www.ebi.ac.uk/pdbsum/6w0t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w0t ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Zhang~~, S]]	+	__TOC__
-	[[Category: Wu, M]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Wu M]]
		+	[[Category: Zhang S]]

OCA at 03:56, 13 May 2020

OCA — Wed, 13 May 2020 03:56:02 GMT

←Older revision		Revision as of 03:56, 13 May 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6w0t is ON HOLD	+	The entry 6w0t is ON HOLD until Paper Publication

	Authors: Wu, M., Zhang, S.		Authors: Wu, M., Zhang, S.

OCA: Protected "6w0t" [edit=sysop:move=sysop]

OCA — Wed, 11 Mar 2020 06:08:03 GMT

Protected "6w0t" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:08, 11 March 2020

OCA: New page: '''Unreleased structure''' The entry 6w0t is ON HOLD Authors: Wu, M., Zhang, S. Description: Co-crystal structures of CHIKV nsP3 macrodomain with pyrimidone fragments [[Category: Unrel...

OCA — Wed, 11 Mar 2020 06:08:02 GMT

New page: '''Unreleased structure''' The entry 6w0t is ON HOLD Authors: Wu, M., Zhang, S. Description: Co-crystal structures of CHIKV nsP3 macrodomain with pyrimidone fragments [[Category: Unrel...

New page

'''Unreleased structure'''

The entry 6w0t is ON HOLD

Authors: Wu, M., Zhang, S.

Description: Co-crystal structures of CHIKV nsP3 macrodomain with pyrimidone fragments
[[Category: Unreleased Structures]]
[[Category: Zhang, S]]
[[Category: Wu, M]]

6w0t - Revision history

OCA at 08:24, 11 October 2023

OCA at 05:49, 20 January 2021

OCA at 03:56, 13 May 2020

OCA: Protected "6w0t" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6w0t is ON HOLD Authors: Wu, M., Zhang, S. Description: Co-crystal structures of CHIKV nsP3 macrodomain with pyrimidone fragments [[Category: Unrel...