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

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Basic information

Entry
Database: PDB / ID: 7zpd
TitleCrystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2293
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-JVC / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 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
DepositionApr 27, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 22, 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

Downloads & links

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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)25,5823
Polymers24,9032
Non-polymers6791
Water4,324240
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4090 Å2
ΔGint-27 kcal/mol
Surface area9420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.712, 60.544, 82.557
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-JVC / 1-[(8R,15S,18S)-15-[[3-(aminomethyl)phenyl]methyl]-18-(4-azanylbutyl)-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: 678.825 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H50N10O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 240 / 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: 2.44 Å3/Da / Density % sol: 49.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1 M sodium acetate 0.2 M ammonium sulfate 11 % PEG2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.82656 Å
DetectorType: DECTRIS PILATUS3 S 2M / Detector: PIXEL / Date: Nov 28, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.82656 Å / Relative weight: 1
ReflectionResolution: 1.4→41.95 Å / Num. obs: 48827 / % possible obs: 99.9 % / Redundancy: 7.98 % / Biso Wilson estimate: 17.75 Å2 / CC1/2: 0.999 / Rsym value: 0.042 / Net I/σ(I): 23.54
Reflection shellResolution: 1.4→1.48 Å / Redundancy: 7.66 % / Mean I/σ(I) obs: 3.42 / Num. unique obs: 7753 / CC1/2: 0.919 / Rsym value: 0.467 / % possible all: 99.6

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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: 1.4→25.06 Å / SU ML: 0.1059 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 12.9027
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1525 2441 5 %
Rwork0.1311 46374 -
obs0.1322 48815 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.54 Å2
Refinement stepCycle: LAST / Resolution: 1.4→25.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1441 0 49 240 1730
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00641587
X-RAY DIFFRACTIONf_angle_d0.92892168
X-RAY DIFFRACTIONf_chiral_restr0.0855240
X-RAY DIFFRACTIONf_plane_restr0.0056299
X-RAY DIFFRACTIONf_dihedral_angle_d19.3208586
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.430.20451390.15232644X-RAY DIFFRACTION98.79
1.43-1.460.18141420.13972689X-RAY DIFFRACTION100
1.46-1.490.17171420.13292694X-RAY DIFFRACTION100
1.49-1.530.16591430.12762714X-RAY DIFFRACTION100
1.53-1.570.15321420.11492714X-RAY DIFFRACTION99.96
1.57-1.620.15021410.11342680X-RAY DIFFRACTION100
1.62-1.670.14361430.10932700X-RAY DIFFRACTION100
1.67-1.730.15091420.10462711X-RAY DIFFRACTION100
1.73-1.80.13731430.10392721X-RAY DIFFRACTION100
1.8-1.880.1431430.10962714X-RAY DIFFRACTION100
1.88-1.980.1471420.11552689X-RAY DIFFRACTION99.23
1.98-2.10.12831430.12122725X-RAY DIFFRACTION100
2.1-2.270.14471450.12072741X-RAY DIFFRACTION99.97
2.27-2.490.17091440.12712752X-RAY DIFFRACTION100
2.49-2.850.14861460.13812761X-RAY DIFFRACTION99.79
2.85-3.590.1751470.14072798X-RAY DIFFRACTION100
3.59-25.060.14111540.14672927X-RAY DIFFRACTION99.84

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