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- PDB-7vlg: Crystal structure of Zika NS2B-NS3 protease with compound MI2201 -

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Basic information

Entry
Database: PDB / ID: 7vlg
TitleCrystal structure of Zika NS2B-NS3 protease with compound MI2201
Components
  • NS3 protease
  • Serine protease subunit NS2B
KeywordsVIRAL PROTEIN / NS3 Protease
Function / homology
Function and homology information


symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / 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 / ribonucleoside triphosphate phosphatase activity / double-stranded RNA binding / viral capsid / nucleoside-triphosphate phosphatase / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / symbiont-mediated suppression of host toll-like receptor signaling pathway ...symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / 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 / ribonucleoside triphosphate phosphatase activity / double-stranded RNA binding / viral capsid / nucleoside-triphosphate phosphatase / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / symbiont-mediated suppression of host toll-like receptor signaling pathway / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / clathrin-dependent endocytosis of virus by host cell / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / protein dimerization activity / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / symbiont entry into host cell / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / serine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / lipid binding / host cell nucleus / virion attachment to host cell / GTP binding / structural molecule activity / virion membrane / ATP hydrolysis activity / proteolysis / extracellular region / ATP binding / membrane / metal ion binding
Similarity search - Function
: / Flavivirus capsid protein C superfamily / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus non-structural protein NS2B / Flavivirus envelope glycoprotein E, stem/anchor domain / : / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A ...: / Flavivirus capsid protein C superfamily / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus non-structural protein NS2B / Flavivirus envelope glycoprotein E, stem/anchor domain / : / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus capsid protein C / 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, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M, flavivirus / Flavivirus envelope glycoprotein M / Envelope glycoprotein M superfamily, flavivirus / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation domain / Flavivirus glycoprotein, central and dimerisation domains / 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-7PZ / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.771 Å
AuthorsQuek, J.P.
Funding support Singapore, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Singapore)NRF2016NRF-CRP001-063 Singapore
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
DepositionOct 2, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 10, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)25,6724
Polymers24,9032
Non-polymers7692
Water1,02757
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4200 Å2
ΔGint-35 kcal/mol
Surface area8920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.979, 60.118, 82.350
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Serine protease subunit NS2B / NS2B cofactor


Mass: 5865.384 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Production host: Escherichia coli (E. coli)
References: UniProt: Q32ZE1, flavivirin, nucleoside-triphosphate phosphatase, RNA helicase, mRNA (guanine-N7)-methyltransferase, methyltransferase cap1, RNA-directed RNA polymerase
#2: Protein NS3 protease


Mass: 19037.592 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus (strain Mr 766) / Strain: Mr 766 / Gene: GP1, A2G93_63394gpGP1 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A142IX72
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-7PZ / 1-[(5~{R},8~{R},15~{S},18~{S})-15,18-bis(4-azanylbutyl)-4,7,14,17,20-pentakis(oxidanylidene)-5-propan-2-yl-3,6,13,16,19-pentazabicyclo[20.3.1]hexacosa-1(25),22(26),23-trien-8-yl]guanidine


Mass: 672.862 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H56N10O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / 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: 2.43 Å3/Da / Density % sol: 49.47 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / Details: 2M Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Nov 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.771→48.56 Å / Num. obs: 24295 / % possible obs: 99.97 % / Redundancy: 12.9 % / CC1/2: 1 / Net I/σ(I): 26.16
Reflection shellResolution: 1.771→1.835 Å / Num. unique obs: 2358 / CC1/2: 0.5

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.16_3549refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5GPI

5gpi


Resolution: 1.771→48.556 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / Phase error: 21.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.197 2285 5 %
Rwork0.1788 43370 -
obs-24295 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 110.82 Å2 / Biso mean: 45.2676 Å2 / Biso min: 26.21 Å2
Refinement stepCycle: final / Resolution: 1.771→48.556 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1421 0 108 57 1586
Biso mean--42.95 47.57 -
Num. residues----192
LS refinement shellResolution: 1.7714→1.8099 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3648 141 -
obs--99 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.9899-4.68933.41497.7696-5.6844.26360.54260.081-0.5255-0.95090.0486-0.41090.84330.0924-0.65930.4911-0.0476-0.04590.3291-0.04810.5517-4.1836-31.80984.1833
23.4996-0.414-0.28176.017.52019.5837-0.0488-0.1975-0.22750.1336-0.2810.27480.8488-0.8110.23710.55790.0118-0.03340.54710.13560.4124-5.1552-27.904918.9574
35.78840.97492.4764.5736-0.47262.82180.7516-1.6791-0.26340.8093-0.8745-0.91580.20150.52050.09590.90090.0513-0.09250.67770.04880.4386-0.7786-18.161328.0777
44.92714.3897-4.71946.2346-2.16846.35630.8622-0.7924-1.63170.7878-0.8154-2.34491.03071.8171-0.26760.7190.048-0.25520.67190.01020.75967.2746-11.973523.6802
59.134-3.3145.48545.0164-5.24766.1064-0.5104-1.13621.02350.86620.3581-0.1362-0.6359-0.78150.44240.5157-0.016-0.04520.4227-0.10410.52663.13490.335215.1096
69.10685.50024.96888.58415.09559.3757-0.48430.68590.8117-0.83910.34090.2616-0.80870.21130.30390.41560.0256-0.03620.36890.07890.4343-3.5607-2.32630.9665
72.77191.2348-2.10595.2944-1.01182.84350.05120.1061-0.9609-0.1817-0.09640.3161.1322-0.35010.35940.4652-0.0262-0.03590.40120.0240.5077-5.7443-30.053810.2235
85.32211.15032.00276.0655-1.60825.940.09860.1036-0.28570.1224-0.00280.03410.2825-0.0679-0.03420.2650.0085-0.00670.2096-0.02630.2351-6.0935-24.08686.3037
99.1853-0.01842.35332.31910.38738.29240.25030.0159-1.0677-0.0383-0.12260.44450.6254-0.4782-0.09840.2687-0.0373-0.00320.3075-0.03680.3897-13.3522-26.46132.0468
103.07671.36992.19163.41052.07464.5775-0.0357-0.4620.11350.4333-0.11170.2971-0.2849-0.50750.16950.36820.09210.05260.3716-0.00550.3468-12.0222-13.375412.0922
114.2329-4.4837-3.93558.97198.16548.5894-0.395-0.7851-0.01551.0270.6914-0.62460.34010.6894-0.14140.46670.0636-0.00750.36680.03220.35472.8746-20.92316.3895
125.60071.40581.19838.4613-2.93335.4484-0.057-0.3380.52130.1589-0.4005-0.9887-0.23130.5860.32380.46780.1160.00410.3583-0.09050.2662-0.0062-7.270917.2212
133.3623-0.066-0.46148.25940.79084.2944-0.1201-0.12490.17660.3999-0.00870.1851-0.236-0.09330.1510.2621-0.0006-0.03210.2729-0.02070.2334-0.7547-9.750610.4347
142.75172.0799-0.10812.86251.88462.3623-0.0059-1.6720.22460.7655-0.0170.4667-0.5105-0.04210.06630.4960.06520.07620.5779-0.03850.3202-7.9768-15.100422.2767
155.69711.5914-2.0125.9725-0.21475.6577-0.1186-0.07290.29060.03740.09440.0622-0.17-0.0230.01710.28030.0547-0.01880.2225-0.02850.2119-1.7422-9.459410.0001
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 50 through 54 )A50 - 54
2X-RAY DIFFRACTION2chain 'A' and (resid 55 through 59 )A55 - 59
3X-RAY DIFFRACTION3chain 'A' and (resid 60 through 64 )A60 - 64
4X-RAY DIFFRACTION4chain 'A' and (resid 65 through 69 )A65 - 69
5X-RAY DIFFRACTION5chain 'A' and (resid 70 through 74 )A70 - 74
6X-RAY DIFFRACTION6chain 'A' and (resid 75 through 87 )A75 - 87
7X-RAY DIFFRACTION7chain 'B' and (resid 17 through 28 )B17 - 28
8X-RAY DIFFRACTION8chain 'B' and (resid 29 through 53 )B29 - 53
9X-RAY DIFFRACTION9chain 'B' and (resid 54 through 71 )B54 - 71
10X-RAY DIFFRACTION10chain 'B' and (resid 72 through 94 )B72 - 94
11X-RAY DIFFRACTION11chain 'B' and (resid 95 through 106 )B95 - 106
12X-RAY DIFFRACTION12chain 'B' and (resid 107 through 118 )B107 - 118
13X-RAY DIFFRACTION13chain 'B' and (resid 119 through 137 )B119 - 137
14X-RAY DIFFRACTION14chain 'B' and (resid 138 through 145 )B138 - 145
15X-RAY DIFFRACTION15chain 'B' and (resid 146 through 170 )B146 - 170

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