Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0180632
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dc.titleSolution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants
dc.contributor.authorRoy A.
dc.contributor.authorLim L.
dc.contributor.authorSrivastava S.
dc.contributor.authorLu Y.
dc.contributor.authorSong J.
dc.date.accessioned2020-03-19T09:01:47Z
dc.date.available2020-03-19T09:01:47Z
dc.date.issued2017
dc.identifier.citationRoy A., Lim L., Srivastava S., Lu Y., Song J. (2017). Solution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants. PLoS ONE 12 (7) : e0180632. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0180632
dc.identifier.issn1932-6203
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/165787
dc.description.abstractThe recent Zika viral (ZIKV) epidemic has been associated with severe neurological pathologies such as neonatal microcephaly and Guillain-Barre syndrome but unfortunately no vaccine or medication is effectively available yet. Zika NS2B-NS3pro is essential for the pro-teolysis of the viral polyprotein and thereby viral replication. Thus NS2B-NS3pro represents an attractive target for anti-Zika drug discovery/design. Here, we have characterized the solution conformations and catalytic parameters of both linked and unlinked Zika NS2B-NS3pro complexes and found that the unlinked complex manifested well-dispersed NMR spectra. Subsequently with selective isotope-labeling using NMR spectroscopy, we demonstrated that C-terminal residues (R73-K100) of NS2B is highly disordered without any stable tertiary and secondary structures in the Zika NS2B-NS3pro complex in the free state. Upon binding to the well-characterized serine protease inhibitor, bovine pancreatic trypsin inhibitor (BPTI), only the extreme C-terminal residues (L86-K100) remain disordered. Additionally, we have identified five flavonoids and one natural phenol rich in edible plants including fruits and vegetables, which inhibit Zika NS2B-NS3pro in a non-competitive mode, with Ki ranging from 770 nM for Myricetin to 34.02 ?M for Apigenin. Molecular docking showed that they all bind to a pocket on the back of the active site and their structure-activity relationship was elucidated. Our study provides valuable insights into the solution conformation of Zika NS2B-NS3pro and further deciphers its susceptibility towards allosteric inhibition by natural products. As these natural product inhibitors fundamentally differ from the currently-known active site inhibitors in terms of both inhibitory mode and chemical scaffold, our finding might open a new avenue for development of better allosteric inhibitors to fight ZIKV infection. © 2017 Roy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.publisherPublic Library of Science
dc.sourceUnpaywall 20200320
dc.subjectapigenin
dc.subjectaprotinin
dc.subjectcatechin
dc.subjectcurcumin
dc.subjectdaidzein
dc.subjectflavonoid
dc.subjectisorhamnetin
dc.subjectluteolin
dc.subjectmyricetin
dc.subjectnatural product
dc.subjectNS2B NS3 protease
dc.subjectphenol
dc.subjectproteinase
dc.subjectquercetin
dc.subjectresveratrol
dc.subjectserine proteinase inhibitor
dc.subjectunclassified drug
dc.subjectbiological product
dc.subjectbuffer
dc.subjectNS2B protein, flavivirus
dc.subjectNS3 protein, flavivirus
dc.subjectRNA helicase
dc.subjectserine proteinase
dc.subjectsolution and solubility
dc.subjectviral protein
dc.subjectArticle
dc.subjectcarboxy terminal sequence
dc.subjectcatalysis
dc.subjectcircular dichroism
dc.subjectdrug identification
dc.subjectenzyme activity
dc.subjectenzyme conformation
dc.subjectenzyme inhibition
dc.subjectenzyme kinetics
dc.subjectfruit
dc.subjectIC50
dc.subjectmolecular cloning
dc.subjectmolecular docking
dc.subjectnonhuman
dc.subjectnuclear magnetic resonance spectroscopy
dc.subjectplasmid
dc.subjectprotein expression
dc.subjectprotein purification
dc.subjectprotein secondary structure
dc.subjectprotein tertiary structure
dc.subjectstructure activity relation
dc.subjectvegetable
dc.subjectZika virus
dc.subjectantagonists and inhibitors
dc.subjectbinding site
dc.subjectbiocatalysis
dc.subjectbiophysics
dc.subjectchemistry
dc.subjectdrug effects
dc.subjectedible plant
dc.subjecthydrogen bond
dc.subjectisolation and purification
dc.subjectkinetics
dc.subjectmetabolism
dc.subjectmolecular model
dc.subjectprotein conformation
dc.subjectsolution and solubility
dc.subjectZika virus
dc.subjectBinding Sites
dc.subjectBiocatalysis
dc.subjectBiological Products
dc.subjectBiophysical Phenomena
dc.subjectBuffers
dc.subjectCloning, Molecular
dc.subjectHydrogen Bonding
dc.subjectKinetics
dc.subjectModels, Molecular
dc.subjectPlants, Edible
dc.subjectProtein Conformation
dc.subjectRNA Helicases
dc.subjectSerine Endopeptidases
dc.subjectSolutions
dc.subjectViral Nonstructural Proteins
dc.subjectZika Virus
dc.typeArticle
dc.contributor.departmentBIOLOGY (NU)
dc.contributor.departmentDEPT OF BIOLOGICAL SCIENCES
dc.description.doi10.1371/journal.pone.0180632
dc.description.sourcetitlePLoS ONE
dc.description.volume12
dc.description.issue7
dc.description.pagee0180632
dc.published.statePublished
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