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- PDB-7obv: Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus i... -

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Basic information

Entry
Database: PDB / ID: 7obv
TitleCrystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2248
Components
  • Inhibitor MI-2248
  • 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
Biological speciesZika virus
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsHuber, S. / Heine, A. / Steinmetzer, T.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Structure-Based Optimization and Characterization of Macrocyclic Zika Virus NS2B-NS3 Protease Inhibitors.
Authors: Huber, S. / Braun, N.J. / Schmacke, L.C. / Quek, J.P. / Murra, R. / Bender, D. / Hildt, E. / Luo, D. / Heine, A. / Steinmetzer, T.
History
DepositionApr 23, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 6, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Data collection / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_conn
Item: _struct_conn.pdbx_leaving_atom_flag

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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
D: Inhibitor MI-2248


Theoretical massNumber of molelcules
Total (without water)25,6253
Polymers25,6253
Non-polymers00
Water4,792266
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4800 Å2
ΔGint-26 kcal/mol
Surface area9020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.089, 61.233, 82.928
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: Protein/peptide Inhibitor MI-2248


Mass: 721.891 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 266 / 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: 2.33 Å3/Da / Density % sol: 47.32 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 0.1 M sodium acetate 0.2 M ammonium sulfate 3 % PEG2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: May 29, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.3→45.1 Å / Num. obs: 57246 / % possible obs: 99.8 % / Redundancy: 8.72 % / Biso Wilson estimate: 15.44 Å2 / CC1/2: 1 / Rsym value: 0.039 / Net I/σ(I): 26.1
Reflection shellResolution: 1.3→1.38 Å / Redundancy: 8.88 % / Mean I/σ(I) obs: 3.9 / Num. unique obs: 9043 / CC1/2: 0.932 / Rsym value: 0.494 / % possible all: 98.9

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5GPI

5gpi


Resolution: 1.3→23.57 Å / SU ML: 0.0948 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 12.3937
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1544 2862 5 %
Rwork0.1273 54369 -
obs0.1286 57231 99.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.46 Å2
Refinement stepCycle: LAST / Resolution: 1.3→23.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1421 0 50 266 1737
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00621591
X-RAY DIFFRACTIONf_angle_d0.95892177
X-RAY DIFFRACTIONf_chiral_restr0.0835242
X-RAY DIFFRACTIONf_plane_restr0.0062295
X-RAY DIFFRACTIONf_dihedral_angle_d23.534586
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.320.20831370.15552589X-RAY DIFFRACTION96.43
1.32-1.350.18981410.14442677X-RAY DIFFRACTION99.93
1.35-1.370.16941430.13452718X-RAY DIFFRACTION99.97
1.37-1.40.15071400.11922659X-RAY DIFFRACTION99.93
1.4-1.430.15531420.1142701X-RAY DIFFRACTION99.89
1.43-1.460.1331410.10732687X-RAY DIFFRACTION100
1.46-1.50.13861420.10272700X-RAY DIFFRACTION100
1.5-1.540.12721420.10152698X-RAY DIFFRACTION100
1.54-1.590.14761420.10182685X-RAY DIFFRACTION100
1.59-1.640.14581420.10572697X-RAY DIFFRACTION100
1.64-1.70.13431420.10452707X-RAY DIFFRACTION100
1.7-1.760.13941430.10422709X-RAY DIFFRACTION100
1.76-1.840.13931430.10722734X-RAY DIFFRACTION100
1.84-1.940.14981430.11642699X-RAY DIFFRACTION99.96
1.94-2.060.1511440.11622741X-RAY DIFFRACTION99.97
2.06-2.220.16061430.12052722X-RAY DIFFRACTION99.97
2.22-2.440.14851450.12752761X-RAY DIFFRACTION100
2.44-2.80.16361460.13972768X-RAY DIFFRACTION99.9
2.8-3.520.15651470.14242797X-RAY DIFFRACTION100
3.52-23.570.16051540.13892920X-RAY DIFFRACTION99.9

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