6y3b: Difference between revisions
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==Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2110== | ==Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2110== | ||
<StructureSection load='6y3b' size='340' side='right'caption='[[6y3b]]' scene=''> | <StructureSection load='6y3b' size='340' side='right'caption='[[6y3b]], [[Resolution|resolution]] 1.59Å' 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=6Y3B OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y3B FirstGlance]. <br> | <table><tr><td colspan='2'>[[6y3b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Zikv Zikv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y3B OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y3B 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=6y3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y3b OCA], [http://pdbe.org/6y3b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y3b RCSB], [http://www.ebi.ac.uk/pdbsum/6y3b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y3b 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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=O7N:1-[(8~{R},15~{S},18~{S})-15,18-bis(4-azanylbutyl)-4,7,14,17,20-pentakis(oxidanylidene)-3,6,13,16,19-pentazabicyclo[20.3.1]hexacosa-1(25),22(26),23-trien-8-yl]guanidine'>O7N</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6y3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y3b OCA], [http://pdbe.org/6y3b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y3b RCSB], [http://www.ebi.ac.uk/pdbsum/6y3b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y3b ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/H8XX12_ZIKV H8XX12_ZIKV]] Peptide 2k: Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[SAAS:SAAS00882589] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A series of cyclic active-site directed inhibitors of the NS2B-NS3 proteases from Zika- (ZIKV), West Nile- (WNV), and Dengue-4 (DENV4) viruses was designed. The most potent compounds contain a reversely incorporated d-lysine residue in P1 position, where its side chain is connected to the P2 backbone, its a-amino group is converted into a guanidine for interaction with the conserved Asp129 side chain in the S1 pocket, and its carboxyl group is used for cyclization to the P3 lysine residue via an appropriate linker segment. The most potent compounds inhibit the ZIKV protease with K i values between 1.5 - 5 nM. Crystal structures of seven ZIKV protease inhibitor complexes were determined to support the design of the inhibitors. The binding mode of these compounds also explains their high selectivity as NS2B-NS3 inhibitors, which possess a negligible inhibitory effect on trypsin-like serine proteases or furin-like proprotein convertases. Although the WNV and DENV4 proteases are less efficiently inhibited, a comparable ranking of the potencies was observed for all three flavivirins suggesting that this compound type could serve as pan-flaviviral protease inhibitors. | |||
Structure-based macrocyclization of substrate analog NS2B-NS3 protease inhibitors of Zika, West Nile and Dengue viruses.,Braun NJ, Quek JP, Huber S, Kouretova J, Rogge D, Lang-Henkel H, Cheong ZKE, Chew BLA, Heine A, Luo D, Steinmetzer T ChemMedChem. 2020 Jun 5. doi: 10.1002/cmdc.202000237. PMID:32501637<ref>PMID:32501637</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6y3b" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Heine A]] | [[Category: Zikv]] | ||
[[Category: Huber S]] | [[Category: Heine, A]] | ||
[[Category: Steinmetzer T]] | [[Category: Huber, S]] | ||
[[Category: Steinmetzer, T]] | |||
[[Category: Flavivirin]] | |||
[[Category: Ns2b-ns3]] | |||
[[Category: Serine protease]] | |||
[[Category: Viral protein]] | |||
[[Category: Zika virus]] | |||
Revision as of 09:41, 19 August 2020
Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2110Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2110
Structural highlights
Function[H8XX12_ZIKV] Peptide 2k: Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[SAAS:SAAS00882589] Publication Abstract from PubMedA series of cyclic active-site directed inhibitors of the NS2B-NS3 proteases from Zika- (ZIKV), West Nile- (WNV), and Dengue-4 (DENV4) viruses was designed. The most potent compounds contain a reversely incorporated d-lysine residue in P1 position, where its side chain is connected to the P2 backbone, its a-amino group is converted into a guanidine for interaction with the conserved Asp129 side chain in the S1 pocket, and its carboxyl group is used for cyclization to the P3 lysine residue via an appropriate linker segment. The most potent compounds inhibit the ZIKV protease with K i values between 1.5 - 5 nM. Crystal structures of seven ZIKV protease inhibitor complexes were determined to support the design of the inhibitors. The binding mode of these compounds also explains their high selectivity as NS2B-NS3 inhibitors, which possess a negligible inhibitory effect on trypsin-like serine proteases or furin-like proprotein convertases. Although the WNV and DENV4 proteases are less efficiently inhibited, a comparable ranking of the potencies was observed for all three flavivirins suggesting that this compound type could serve as pan-flaviviral protease inhibitors. Structure-based macrocyclization of substrate analog NS2B-NS3 protease inhibitors of Zika, West Nile and Dengue viruses.,Braun NJ, Quek JP, Huber S, Kouretova J, Rogge D, Lang-Henkel H, Cheong ZKE, Chew BLA, Heine A, Luo D, Steinmetzer T ChemMedChem. 2020 Jun 5. doi: 10.1002/cmdc.202000237. PMID:32501637[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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