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- PDB-8a15: Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus i... -

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Basic information

Entry
Database: PDB / ID: 8a15
TitleCrystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2230
Components
  • Serine protease NS3
  • Serine protease subunit NS2B
KeywordsVIRAL PROTEIN / FLAVIVIRIN / SERINE PROTEASE / NS2B-NS3 / ZIKA VIRUS
Function / homology
Function and homology information


symbiont-mediated suppression of host interferon-mediated signaling pathway / flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / viral capsid / double-stranded RNA binding / nucleoside-triphosphate phosphatase / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / protein-macromolecule adaptor activity ...symbiont-mediated suppression of host interferon-mediated signaling pathway / flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / viral capsid / double-stranded RNA binding / nucleoside-triphosphate phosphatase / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / protein-macromolecule adaptor activity / symbiont-mediated suppression of host toll-like receptor signaling pathway / clathrin-dependent endocytosis of virus by host cell / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / methyltransferase cap1 activity / host cell cytoplasm / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / protein dimerization activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / serine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / viral envelope / lipid binding / GTP binding / virion attachment to host cell / host cell nucleus / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / extracellular region / ATP binding / metal ion binding / membrane
Similarity search - Function
Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / : / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A ...Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / : / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus NS2B domain profile. / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS2A / Flavivirus non-structural protein NS2A / Flavivirus NS3, petidase S7 / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus NS3 protease (NS3pro) domain profile. / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus capsid protein C / Flavivirus capsid protein C / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M, flavivirus / Envelope glycoprotein M superfamily, flavivirus / Flavivirus envelope glycoprotein M / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flavivirus envelope glycoprotein E, stem/anchor domain / : / Flavivirus NS3 helicase, C-terminal helical domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation domain / Flavivirus glycoprotein, central and dimerisation domains / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Ribosomal RNA methyltransferase, FtsJ domain / FtsJ-like methyltransferase / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Immunoglobulin E-set / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-KPO / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.23 Å
AuthorsHuber, S. / Steinmetzer, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Arch Pharm / Year: 2024
Title: Synthesis and structural characterization of new macrocyclic inhibitors of the Zika virus NS2B-NS3 protease.
Authors: Huber, S. / Braun, N.J. / Schmacke, L.C. / Murra, R. / Bender, D. / Hildt, E. / Heine, A. / Steinmetzer, T.
History
DepositionMay 31, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Jun 12, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine protease subunit NS2B
B: Serine protease NS3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6033
Polymers24,9032
Non-polymers7001
Water4,306239
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.333, 60.535, 81.753
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Serine protease subunit NS2B / Flavivirin protease NS2B regulatory subunit / Non-structural protein 2B


Mass: 5865.384 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Plasmid: bZiPro / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q32ZE1
#2: Protein Serine protease NS3 / Flavivirin protease NS3 catalytic subunit / Non-structural protein 3


Mass: 19037.592 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Plasmid: bZiPro / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q32ZE1, flavivirin, nucleoside-triphosphate phosphatase, RNA helicase
#3: Chemical ChemComp-KPO / 1-[(8~{R},15~{S},18~{S})-15-(4-azanylbutyl)-18-(naphthalen-2-ylmethyl)-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


Mass: 699.842 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H49N9O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 239 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.45 Å3/Da / Density % sol: 49.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 0.1 M sodium acetate pH 4.6 0.2 M ammonium sulfate 21% PEG2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.8266 Å
DetectorType: DECTRIS PILATUS3 S 2M / Detector: PIXEL / Date: Nov 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8266 Å / Relative weight: 1
ReflectionResolution: 1.23→42.24 Å / Num. obs: 71889 / % possible obs: 99.8 % / Redundancy: 6.51 % / Biso Wilson estimate: 15.66 Å2 / CC1/2: 0.999 / Rsym value: 0.048 / Net I/σ(I): 17.6
Reflection shellResolution: 1.23→1.3 Å / Redundancy: 6.39 % / Mean I/σ(I) obs: 2.8 / Num. unique obs: 11354 / CC1/2: 0.894 / Rsym value: 0.498 / % possible all: 98.7

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5GPI

5gpi


Resolution: 1.23→19.37 Å / SU ML: 0.0922 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 11.8938
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1465 3593 5 %
Rwork0.1332 68272 -
obs0.1339 71865 99.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.38 Å2
Refinement stepCycle: LAST / Resolution: 1.23→19.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1402 0 51 239 1692
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00611584
X-RAY DIFFRACTIONf_angle_d0.97362165
X-RAY DIFFRACTIONf_chiral_restr0.0862236
X-RAY DIFFRACTIONf_plane_restr0.0061304
X-RAY DIFFRACTIONf_dihedral_angle_d19.7492588
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.23-1.240.20241300.19522460X-RAY DIFFRACTION94.63
1.24-1.260.20371360.16822598X-RAY DIFFRACTION99.89
1.26-1.280.17471370.16122591X-RAY DIFFRACTION99.96
1.28-1.30.17081380.14862620X-RAY DIFFRACTION99.96
1.3-1.320.18041350.1452574X-RAY DIFFRACTION99.96
1.32-1.340.17491380.14162612X-RAY DIFFRACTION100
1.34-1.360.16321370.13092606X-RAY DIFFRACTION99.96
1.36-1.390.14051360.12372585X-RAY DIFFRACTION100
1.39-1.420.1341380.12272633X-RAY DIFFRACTION100
1.42-1.440.13821370.11592601X-RAY DIFFRACTION100
1.44-1.480.15031370.11662603X-RAY DIFFRACTION100
1.48-1.510.12581380.1052609X-RAY DIFFRACTION100
1.51-1.550.13931370.10282606X-RAY DIFFRACTION100
1.55-1.590.12221390.1032646X-RAY DIFFRACTION100
1.59-1.640.12211370.10512597X-RAY DIFFRACTION99.96
1.64-1.690.13831370.10512615X-RAY DIFFRACTION100
1.69-1.750.14041380.11082613X-RAY DIFFRACTION99.96
1.75-1.820.13711400.11522657X-RAY DIFFRACTION99.96
1.82-1.90.14821380.12062621X-RAY DIFFRACTION100
1.9-20.12021390.122645X-RAY DIFFRACTION100
2-2.130.15311380.12742621X-RAY DIFFRACTION100
2.13-2.290.14221400.12772664X-RAY DIFFRACTION99.96
2.29-2.520.16951410.13992680X-RAY DIFFRACTION99.93
2.52-2.890.171410.142677X-RAY DIFFRACTION100
2.89-3.630.14251430.14252707X-RAY DIFFRACTION99.89
3.63-19.370.13881480.14882831X-RAY DIFFRACTION99.77

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