6mo2: Difference between revisions
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The | ==Structure of dengue virus protease with an allosteric Inhibitor that blocks replication== | ||
<StructureSection load='6mo2' size='340' side='right'caption='[[6mo2]], [[Resolution|resolution]] 2.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6mo2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Dengue_virus_2 Dengue virus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MO2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MO2 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JVM:1-(4-{5-[(piperidin-4-yl)methoxy]-3-[4-(1H-pyrazol-4-yl)phenyl]pyrazin-2-yl}phenyl)methanamine'>JVM</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=6mo2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mo2 OCA], [https://pdbe.org/6mo2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mo2 RCSB], [https://www.ebi.ac.uk/pdbsum/6mo2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mo2 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A0B4L2Y4_9FLAV A0A0B4L2Y4_9FLAV] [https://www.uniprot.org/uniprot/Q91H74_9FLAV Q91H74_9FLAV] 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 (By similarity).[SAAS:SAAS026470_004_099774] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Flaviviruses, including dengue, West Nile and recently emerged Zika virus, are important human pathogens, but there are no drugs to prevent or treat these viral infections. The highly conserved Flavivirus NS2B-NS3 protease is essential for viral replication and therefore a drug target. Compound screening followed by medicinal chemistry yielded a series of drug-like, broadly active inhibitors of Flavivirus proteases with IC50 as low as 120 nM. The inhibitor exhibited significant antiviral activities in cells (EC68: 300-600 nM) and in a mouse model of Zika virus infection. X-ray studies reveal that the inhibitors bind to an allosteric, mostly hydrophobic pocket of dengue NS3 and hold the protease in an open, catalytically inactive conformation. The inhibitors and their binding structures would be useful for rational drug development targeting Zika, dengue and other Flaviviruses. | |||
Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease.,Yao Y, Huo T, Lin YL, Nie S, Wu F, Hua Y, Wu J, Kneubehl AR, Vogt MB, Rico-Hesse R, Song Y J Am Chem Soc. 2019 May 1;141(17):6832-6836. doi: 10.1021/jacs.9b02505. Epub 2019, Apr 23. PMID:31017399<ref>PMID:31017399</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6mo2" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Virus protease 3D structures|Virus protease 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Dengue virus 2]] | |||
[[Category: Large Structures]] | |||
[[Category: Hua Y]] | |||
[[Category: Huo T]] | |||
[[Category: Lin Y-L]] | |||
[[Category: Nie S]] | |||
[[Category: Song Y]] | |||
[[Category: Wu F]] | |||
[[Category: Wu J]] | |||
[[Category: Yao Y]] | |||
Latest revision as of 09:35, 11 October 2023
Structure of dengue virus protease with an allosteric Inhibitor that blocks replicationStructure of dengue virus protease with an allosteric Inhibitor that blocks replication
Structural highlights
FunctionA0A0B4L2Y4_9FLAV Q91H74_9FLAV 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 (By similarity).[SAAS:SAAS026470_004_099774] Publication Abstract from PubMedFlaviviruses, including dengue, West Nile and recently emerged Zika virus, are important human pathogens, but there are no drugs to prevent or treat these viral infections. The highly conserved Flavivirus NS2B-NS3 protease is essential for viral replication and therefore a drug target. Compound screening followed by medicinal chemistry yielded a series of drug-like, broadly active inhibitors of Flavivirus proteases with IC50 as low as 120 nM. The inhibitor exhibited significant antiviral activities in cells (EC68: 300-600 nM) and in a mouse model of Zika virus infection. X-ray studies reveal that the inhibitors bind to an allosteric, mostly hydrophobic pocket of dengue NS3 and hold the protease in an open, catalytically inactive conformation. The inhibitors and their binding structures would be useful for rational drug development targeting Zika, dengue and other Flaviviruses. Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease.,Yao Y, Huo T, Lin YL, Nie S, Wu F, Hua Y, Wu J, Kneubehl AR, Vogt MB, Rico-Hesse R, Song Y J Am Chem Soc. 2019 May 1;141(17):6832-6836. doi: 10.1021/jacs.9b02505. Epub 2019, Apr 23. PMID:31017399[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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