6kpq

From Proteopedia

(Difference between revisions)

Revision as of 06:30, 19 August 2020

Crystal structure of Zika NS2B-NS3 protease with compound 8

Structural highlights

6kpq is a 2 chain structure with sequence from Zikv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	GP1, A2G93_63394gpGP1 (ZIKV)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Braun NJ, Quek JP, Huber S, Kouretova J, Rogge D, Lang-Henkel H, Cheong ZKE, Chew BLA, Heine A, Luo D, Steinmetzer T. Structure-based macrocyclization of substrate analog NS2B-NS3 protease inhibitors of Zika, West Nile and Dengue viruses. ChemMedChem. 2020 Jun 5. doi: 10.1002/cmdc.202000237. PMID:32501637 doi:http://dx.doi.org/10.1002/cmdc.202000237

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6kpq"

@@ Line 1: / Line 1: @@
 ==Crystal structure of Zika NS2B-NS3 protease with compound 8==
-<StructureSection load='6kpq' size='340' side='right'caption='[[6kpq]]' scene=''>
+<StructureSection load='6kpq' size='340' side='right'caption='[[6kpq]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KPQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6KPQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6kpq]] 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=6KPQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6KPQ 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=6kpq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kpq OCA], [http://pdbe.org/6kpq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kpq RCSB], [http://www.ebi.ac.uk/pdbsum/6kpq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kpq 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=DT0:1-[(10~{R},17~{S},20~{S})-17,20-bis(4-azanylbutyl)-4,9,16,19,22-pentakis(oxidanylidene)-3,8,15,18,21-pentazabicyclo[22.3.1]octacosa-1(27),24(28),25-trien-10-yl]guanidine'>DT0</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GP1, A2G93_63394gpGP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=64320 ZIKV])</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=6kpq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kpq OCA], [http://pdbe.org/6kpq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kpq RCSB], [http://www.ebi.ac.uk/pdbsum/6kpq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kpq ProSAT]</span></td></tr>
 </table>
+== Function ==
+[[http://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]
+<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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6kpq" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Quek JP]]
+[[Category: Zikv]]
+[[Category: Quek, J P]]
+[[Category: Protease inhibitor complex]]
+[[Category: Viral protease]]
+[[Category: Viral protein]]

6kpq

From Proteopedia

Revision as of 06:30, 19 August 2020

Crystal structure of Zika NS2B-NS3 protease with compound 8

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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