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5zmq

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Revision as of 21:21, 28 October 2020

Crystal structure of Zika NS3 protease with phenylacetyl-Lys-Lys-Arg-COOH inhibitor

Structural highlights

5zmq is a 10 chain structure with sequence from Zikv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:	, ,
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] [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 PubMed

Zika virus NS2B-NS3 protease plays an essential role in viral replication by processing the viral polyprotein into individual proteins. The viral protease is therefore considered as an ideal antiviral drug target. To facilitate the development of protease inhibitors, we report three high-resolution co-crystal structures of bZiPro with peptidomimetic inhibitors composed of a P1-P4 segment and different P1' residues. Compounds 1 and 2 possess small P1' groups that are split off by bZiPro, which could be detected by mass spectrometry. On the other hand, the more potent compound 3 contains a bulky P1' benzylamide structure that is resistant to cleavage by bZiPro, demonstrating that presence of an uncleavable C-terminal cap contributes to a slightly improved inhibitory potency. The N-terminal phenylacetyl residue occupies a position above the P1 side chain and therefore stabilizes a horseshoe-like backbone conformation of the bound inhibitors. The P4 moieties show unique intra- and intermolecular interactions. Our work reports the detailed binding mode interactions of substrate-analogue inhibitors within the S4-S1' pockets and explains the preference of bZiPro for basic P1-P3 residues. These new structures of protease-inhibitor complexes will guide the design of more effective NS2B-NS3 protease inhibitors with improved potency and bioavailability.

Structures of Zika virus NS2B-NS3 protease in complex with peptidomimetic inhibitors.,Phoo WW, Zhang Z, Wirawan M, Chew EJC, Chew ABL, Kouretova J, Steinmetzer T, Luo D Antiviral Res. 2018 Oct 10;160:17-24. doi: 10.1016/j.antiviral.2018.10.006. PMID:30315877^[1]

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

References

↑ Phoo WW, Zhang Z, Wirawan M, Chew EJC, Chew ABL, Kouretova J, Steinmetzer T, Luo D. Structures of Zika virus NS2B-NS3 protease in complex with peptidomimetic inhibitors. Antiviral Res. 2018 Oct 10;160:17-24. doi: 10.1016/j.antiviral.2018.10.006. PMID:30315877 doi:http://dx.doi.org/10.1016/j.antiviral.2018.10.006

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/5zmq"

@@ Line 1: / Line 1: @@
 ==Crystal structure of Zika NS3 protease with phenylacetyl-Lys-Lys-Arg-COOH inhibitor==
-<StructureSection load='5zmq' size='340' side='right' caption='[[5zmq]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
+<StructureSection load='5zmq' size='340' side='right'caption='[[5zmq]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5zmq]] is a 10 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=5ZMQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZMQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5zmq]] is a 10 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=5ZMQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5ZMQ FirstGlance]. <br>
 </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DAR:D-ARGININE'>DAR</scene>, <scene name='pdbligand=DLY:D-LYSINE'>DLY</scene>, <scene name='pdbligand=PAC:2-PHENYLACETIC+ACID'>PAC</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5zmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zmq OCA], [http://pdbe.org/5zmq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zmq RCSB], [http://www.ebi.ac.uk/pdbsum/5zmq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zmq ProSAT]</span></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=5zmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zmq OCA], [http://pdbe.org/5zmq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zmq RCSB], [http://www.ebi.ac.uk/pdbsum/5zmq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zmq ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Zikv]]
 [[Category: Phoo, W W]]

5zmq

From Proteopedia

Revision as of 21:21, 28 October 2020

Crystal structure of Zika NS3 protease with phenylacetyl-Lys-Lys-Arg-COOH inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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