View source for 7zno


==Crystal Structure of Unlinked NS2B_NS3 Protease from Zika Virus in Complex with Boronate Inhibitor MI-2270==
<StructureSection load='7zno' size='340' side='right'caption='[[7zno]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7zno]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Zika_virus Zika virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZNO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZNO 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]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JQI:[(1~{R})-1-[[(2~{S})-6-azanyl-2-[[(2~{S})-6-azanyl-2-[2-[3-(4-carbamimidamido-3-oxidanylidene-pentyl)phenyl]ethanoylamino]hexanoyl]amino]hexanoyl]amino]-3-methyl-butyl]boronic+acid'>JQI</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=7zno FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zno OCA], [https://pdbe.org/7zno PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zno RCSB], [https://www.ebi.ac.uk/pdbsum/7zno PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zno ProSAT]</span></td></tr>
</table>
== 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]
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== Publication Abstract from PubMed ==
The Zika virus (ZIKV) remains a potential threat to the public health due to the lack of both an approved vaccination or a specific treatment. In this work, a series of peptidic inhibitors of the ZIKV protease with boroleucine as P1 residue was synthesized. The highest affinities with K(i) values down to 8 nM were observed for compounds with basic residues in both P2 and P3 position and at the N-terminus. The low potency of reference compounds containing leucine, leucine-amide or isopentylamide as P1 residue suggested a covalent binding mode of the boroleucine-derived inhibitors. This was finally proven by crystal structure determination of the most potent inhibitor from this series in complex with the ZIKV protease.

Boroleucine-Derived Covalent Inhibitors of the ZIKV Protease.,Braun NJ, Huber S, Schmacke LC, Heine A, Steinmetzer T ChemMedChem. 2023 Feb 1;18(3):e202200336. doi: 10.1002/cmdc.202200336. Epub 2022 , Nov 21. PMID:36325810<ref>PMID:36325810</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7zno" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Zika virus]]
[[Category: Heine A]]
[[Category: Huber S]]
[[Category: Steinmetzer T]]