8aqa - Revision history

OCA at 05:17, 12 June 2024

2024-06-12T05:17:10Z

← Older revision		Revision as of 05:17, 12 June 2024
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	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8aqa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aqa OCA], [https://pdbe.org/8aqa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aqa RCSB], [https://www.ebi.ac.uk/pdbsum/8aqa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aqa 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=8aqa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aqa OCA], [https://pdbe.org/8aqa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aqa RCSB], [https://www.ebi.ac.uk/pdbsum/8aqa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aqa ProSAT]</span></td></tr>
	</table>		</table>
	== ~~Function~~ ==		<div style="background-color:#fffaf0;">
	~~[https://www~~.~~uniprot.org/uniprot/POLG_ZIKV POLG_ZIKV] Protein C: Encapsulates~~ the ~~genomic RNA~~.~~[UniProtKB:P17763] prM: Acts as a chaperone for envelope protein E during intracellular virion assembly by masking~~ and ~~inactivating envelope protein E fusion peptide~~. ~~prM is matured in~~ the ~~last step~~ of ~~virion assembly~~, ~~presumably~~ to ~~avoid catastrophic activation of~~ the ~~viral fusion peptide induced by~~ the ~~acidic pH~~ of the ~~trans-Golgi network~~. ~~After cleavage by host furin,~~ the ~~pr peptide is released~~ in the ~~extracellular medium and small envelope protein M and envelope protein E homodimers are dissociated~~.~~[UniProtKB:P17763] Envelope protein E: Binding to host~~ cell ~~surface receptor is followed by virus internalization through clathrin-mediated endocytosis~~. ~~Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as~~ a ~~homodimer~~ with ~~prM which acts as~~ a ~~chaperone for envelope protein E~~. ~~After cleavage~~ of ~~prM~~, ~~envelope protein E dissociate from small envelope protein M and homodimerizes~~.~~[UniProtKB:P17763] Non~~-structural ~~protein 1: Involved in virus replication and regulation~~ of the ~~innate immune response~~.~~[UniProtKB~~:~~P17763] Non-structural protein 2A~~: ~~May be involved viral RNA replication and capsid assembly~~.~~[UniProtKB~~:~~P09732] Non-structural protein 4A~~: ~~Induces host endoplasmic reticulum membrane rearrangements leading to the formation of virus-induced membranous vesicles hosting the dsRNA and polymerase~~, ~~functioning as~~ a ~~replication complex. NS4A might also regulate the ATPase activity~~ of the ~~helicase region of Serine protease NS3 chain~~.~~[UniProtKB:P17763] Peptide 2k: Functions as a signal peptide for NS4B and is required for the interferon antagonism activity~~ of ~~the latter~~.~~[UniProtKB:P17763] Non~~-~~structural protein 4B~~: ~~Inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha~~/~~beta pathway.[UniProtKB:P17763]~~		== Publication Abstract from PubMed ==
			Three new series of macrocyclic active site-directed inhibitors of the Zika virus (ZIKV) NS2B-NS3 protease were synthesized. First, attempts were made to replace the basic P3 lysine residue of our previously described inhibitors with uncharged and more hydrophobic residues. This provided numerous compounds with inhibition constants between 30 and 50 nM. A stronger reduction of the inhibitory potency was observed when the P2 lysine was replaced by neutral residues, all of these inhibitors possess K(i) values >1 microM. However, it is possible to replace the P2 lysine with the less basic 3-aminomethylphenylalanine, which provides a similarly potent inhibitor of the ZIKV protease (K(i) = 2.69 nM). Crystal structure investigations showed that the P2 benzylamine structure forms comparable interactions with the protease as lysine. Twelve additional structures of these inhibitors in complex with the protease were determined, which explain many, but not all, SAR data obtained in this study. All individual modifications in the P2 or P3 position resulted in inhibitors with low antiviral efficacy in cell culture. Therefore, a third inhibitor series with combined modifications was synthesized; all of them contain a more hydrophobic d-cyclohexylalanine in the linker segment. At a concentration of 40 microM, two of these compounds possess similar antiviral potency as ribavirin at 100 microM. Due to their reliable crystallization in complex with the ZIKV protease, these cyclic compounds are very well suited for a rational structure-based development of improved inhibitors.

			Synthesis and structural characterization of new macrocyclic inhibitors of the Zika virus NS2B-NS3 protease.,Huber S, Braun NJ, Schmacke LC, Murra R, Bender D, Hildt E, Heine A, Steinmetzer T Arch Pharm (Weinheim). 2024 May 29:e2400250. doi: 10.1002/ardp.202400250. PMID:38809037<ref>PMID:38809037</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 8aqa" style="background-color:#fffaf0;"></div>
			== References ==
			<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 11:23, 15 November 2023

2023-11-15T11:23:59Z

← Older revision		Revision as of 11:23, 15 November 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[8aqa]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Zika_virus Zika virus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8AQA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AQA FirstGlance]. <br>		<table><tr><td colspan='2'>[[8aqa]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Zika_virus Zika virus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8AQA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AQA FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LDO:6-HYDROXY-L-NORLEUCINE'>LDO</scene>, <scene name='pdbligand=V7T:(2R)-6-azanyl-2-carbamimidamido-hexanoic+acid'>V7T</scene>, <scene name='pdbligand=V8N:2-[3-(aminomethyl)phenyl]ethanoic+acid'>V8N</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]] 1.35Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LDO:6-HYDROXY-L-NORLEUCINE'>LDO</scene>, <scene name='pdbligand=V7T:(2R)-6-azanyl-2-carbamimidamido-hexanoic+acid'>V7T</scene>, <scene name='pdbligand=V8N:2-[3-(aminomethyl)phenyl]ethanoic+acid'>V8N</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=8aqa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aqa OCA], [https://pdbe.org/8aqa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aqa RCSB], [https://www.ebi.ac.uk/pdbsum/8aqa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aqa 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=8aqa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aqa OCA], [https://pdbe.org/8aqa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aqa RCSB], [https://www.ebi.ac.uk/pdbsum/8aqa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aqa ProSAT]</span></td></tr>
	</table>		</table>

OCA at 09:27, 21 December 2022

2022-12-21T09:27:09Z

← Older revision		Revision as of 09:27, 21 December 2022
Line 1:		Line 1:
	~~'''Unreleased structure'''~~

	~~The entry~~ 8aqa is ~~ON HOLD~~		==Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2260==
			<StructureSection load='8aqa' size='340' side='right'caption='[[8aqa]], [[Resolution\|resolution]] 1.35Å' scene=''>
	~~Authors~~: ~~Huber~~, S., ~~Steinmetzer~~, T.		== Structural highlights ==
			<table><tr><td colspan='2'>[[8aqa]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Zika_virus Zika virus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8AQA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AQA FirstGlance]. <br>
	~~Description~~: ~~Crystal Structure~~ of ~~Unlinked NS2B~~-~~NS3 Protease~~ from ~~Zika Virus~~ in ~~Complex with Inhibitor MI~~-~~2260~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LDO:6-HYDROXY-L-NORLEUCINE'>LDO</scene>, <scene name='pdbligand=V7T:(2R)-6-azanyl-2-carbamimidamido-hexanoic+acid'>V7T</scene>, <scene name='pdbligand=V8N:2-[3-(aminomethyl)phenyl]ethanoic+acid'>V8N</scene></td></tr>
	[[Category: ~~Unreleased~~ Structures]]		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8aqa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8aqa OCA], [https://pdbe.org/8aqa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8aqa RCSB], [https://www.ebi.ac.uk/pdbsum/8aqa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8aqa ProSAT]</span></td></tr>
	[[Category: ~~Steinmetzer, T~~]]		</table>
	[[Category: Huber, S]]		== Function ==
			[https://www.uniprot.org/uniprot/POLG_ZIKV POLG_ZIKV] Protein C: Encapsulates the genomic RNA.[UniProtKB:P17763] prM: Acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is matured in the last step of virion assembly, presumably to avoid catastrophic activation of the viral fusion peptide induced by the acidic pH of the trans-Golgi network. After cleavage by host furin, the pr peptide is released in the extracellular medium and small envelope protein M and envelope protein E homodimers are dissociated.[UniProtKB:P17763] Envelope protein E: Binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes.[UniProtKB:P17763] Non-structural protein 1: Involved in virus replication and regulation of the innate immune response.[UniProtKB:P17763] Non-structural protein 2A: May be involved viral RNA replication and capsid assembly.[UniProtKB:P09732] Non-structural protein 4A: Induces host endoplasmic reticulum membrane rearrangements leading to the formation of virus-induced membranous vesicles hosting the dsRNA and polymerase, functioning as a replication complex. NS4A might also regulate the ATPase activity of the helicase region of Serine protease NS3 chain.[UniProtKB:P17763] Peptide 2k: Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[UniProtKB:P17763] Non-structural protein 4B: Inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway.[UniProtKB:P17763]
			__TOC__
			</StructureSection>
			[[Category: Large Structures]]
			[[Category: Synthetic construct]]
			[[Category: Zika virus]]
			[[Category: Huber S]]
			[[Category: Steinmetzer T]]

OCA: Protected "8aqa" [edit=sysop:move=sysop]

2022-08-18T03:56:44Z

Protected "8aqa" [edit=sysop:move=sysop]

← Older revision	Revision as of 03:56, 18 August 2022
(No difference)

OCA: New page: '''Unreleased structure''' The entry 8aqa is ON HOLD Authors: Huber, S., Steinmetzer, T. Description: Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with In...

2022-08-18T03:56:42Z

New page: '''Unreleased structure''' The entry 8aqa is ON HOLD Authors: Huber, S., Steinmetzer, T. Description: Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with In...

New page

'''Unreleased structure'''

The entry 8aqa is ON HOLD

Authors: Huber, S., Steinmetzer, T.

Description: Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2260
[[Category: Unreleased Structures]]
[[Category: Steinmetzer, T]]
[[Category: Huber, S]]