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- PDB-7vli: Crystal structure of Zika NS2B-NS3 protease with compound MI2220 -

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Basic information

Entry
Database: PDB / ID: 7vli
TitleCrystal structure of Zika NS2B-NS3 protease with compound MI2220
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 / 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 / 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 / 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 / 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 / RNA helicase / symbiont entry into host cell / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / lipid binding / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / virion attachment to host cell / GTP binding / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / extracellular region / ATP binding / membrane / metal ion binding
Similarity search - Function
: / Flavivirus envelope glycoprotein E, stem/anchor domain / 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 NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A ...: / Flavivirus envelope glycoprotein E, stem/anchor domain / 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 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. / Envelope glycoprotein M, flavivirus / Flavivirus envelope glycoprotein M / 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 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-7QG / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.385 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)25,6114
Polymers24,9032
Non-polymers7082
Water1448
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3920 Å2
ΔGint-37 kcal/mol
Surface area8720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.450, 42.450, 215.734
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number95
Space group name H-MP4322

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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-7QG / 1-[(3~{S},6~{S},19~{R})-3,6-bis(4-azanylbutyl)-2,5,8,12,15,18-hexakis(oxidanylidene)-1,4,7,11,14,17-hexazacyclotricos-19-yl]guanidine


Mass: 611.737 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H49N11O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 8 / 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: 1.95 Å3/Da / Density % sol: 36.97 %
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: 2.385→41.65 Å / Num. obs: 8604 / % possible obs: 99.59 % / Redundancy: 24 % / CC1/2: 0.999 / Net I/σ(I): 14.49
Reflection shellResolution: 2.385→2.47 Å / Num. unique obs: 812 / CC1/2: 0.759

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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: 2.385→41.65 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 31.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2879 750 5.01 %
Rwork0.2301 14203 -
obs-8579 99.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 102.34 Å2 / Biso mean: 54.4095 Å2 / Biso min: 35.91 Å2
Refinement stepCycle: final / Resolution: 2.385→41.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1353 0 96 8 1457
Biso mean--65.7 49.9 -
Num. residues----190
LS refinement shellResolution: 2.3851→2.47 Å /
Rfactor% reflection
Rfree0.4422 -
Rwork0.3885 -
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)
11.8854-0.2048-0.16260.60350.12432.18440.34670.51281.8175-0.4822-1.0371-0.274-0.4921-0.5653-0.08010.99980.18970.18770.5303-0.00320.8237-24.354515.0197-13.9681
24.696-0.31851.3760.1593-0.95726.2267-0.4976-0.5572-0.15331.56850.36321.28040.6963-0.5987-0.43570.61240.03380.01110.59380.06080.6677-28.32054.6001-24.0787
36.66922.88484.08383.245612.80830.2430.78661.8728-1.62621.0142-0.2750.60460.30471.99410.88890.1093-0.18410.9729-0.19310.4774-23.2123-4.6611-31.985
46.92111.8161.81924.32546.31669.2484-1.07072.95482.2357-1.9749-0.1653-1.0212-1.7276-0.1689-0.09611.08570.2120.20960.77420.14350.6183-12.3441-3.1174-33.2528
53.5396-3.1328-0.66684.19520.80351.38451.12170.42271.7498-1.042-0.79650.21710.18870.0134-0.07860.53740.07430.2670.61560.00740.9205-3.3721-9.7862-22.5231
68.1958-2.4444-0.92835.26044.11024.31720.0044-1.07860.0880.84820.2588-1.06840.70440.2409-0.41510.53640.06160.03280.77260.04020.5339-3.6267-4.8594-7.4935
74.1524.17862.57585.33523.21213.83830.3769-0.39980.5413-0.0193-0.57510.72020.0031-0.37840.19690.6690.1243-0.03490.54960.08020.553-26.93138.8761-17.7186
84.80860.11-1.36860.9733-2.25947.38030.2637-0.30851.0225-0.1742-0.21690.3205-0.64780.3695-0.29470.44020.10220.07520.5274-0.03140.4706-20.073412.7323-15.7335
97.49661.91-1.00783.124-1.02935.3352-0.147-0.26450.21620.15780.1494-0.05690.25720.0933-0.19970.52220.08920.0270.52860.00860.458-21.98983.4716-10.2817
101.79332.2661-2.74045.243-1.5816.0204-0.35670.93251.0663-0.06730.29350.5287-0.2423-0.3174-0.57770.9324-0.00730.18880.5664-0.00310.881-25.468712.4896-8.1771
113.5943.1715-2.45553.0935-0.44925.48360.4335-0.15120.67680.035-0.20950.439-0.2627-0.1736-0.29070.5493-0.06160.04280.568-0.04360.5235-26.05734.0973-3.8062
123.3624-0.8189-0.55661.83442.87054.01470.0058-0.1335-0.2656-0.07310.01790.14220.35810.0631-0.14320.52130.02410.00320.45320.12650.4316-20.6352-5.8018-12.6229
133.15110.7449-2.68632.312-2.59582.92680.31340.60960.1914-1.0714-0.4315-0.40260.024-0.11430.02010.44810.0885-0.0290.5210.00780.468-17.78194.5909-26.0395
144.20160.0126-1.28173.63111.66410.9799-0.1975-0.2008-0.0669-0.42670.1334-0.27950.2338-0.34470.09540.5610.09950.0260.4110.04720.4404-11.2745-7.6813-23.1153
153.2856-0.92331.64783.24312.43253.6644-0.03830.0551-0.1876-0.3786-0.06530.10590.22560.4665-0.0330.45830.12790.14050.61370.0820.4954-10.6155-2.1941-18.178
165.88310.87450.48774.28691.31586.02050.32730.5072-0.13570.0248-0.19180.29440.1803-0.27920.01880.59550.08790.00430.4727-0.03410.4351-17.496-4.6725-19.7024
176.84680.13710.01476.89830.57269.23480.54020.59640.235-0.1371-0.0865-0.3711-0.54351.3019-0.40960.58210.05630.05030.620.0140.3582-7.3768-2.8247-17.8458
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 27 )B17 - 27
8X-RAY DIFFRACTION8chain 'B' and (resid 28 through 42 )B28 - 42
9X-RAY DIFFRACTION9chain 'B' and (resid 43 through 53 )B43 - 53
10X-RAY DIFFRACTION10chain 'B' and (resid 54 through 62 )B54 - 62
11X-RAY DIFFRACTION11chain 'B' and (resid 63 through 71 )B63 - 71
12X-RAY DIFFRACTION12chain 'B' and (resid 72 through 94 )B72 - 94
13X-RAY DIFFRACTION13chain 'B' and (resid 95 through 106 )B95 - 106
14X-RAY DIFFRACTION14chain 'B' and (resid 107 through 118 )B107 - 118
15X-RAY DIFFRACTION15chain 'B' and (resid 119 through 137 )B119 - 137
16X-RAY DIFFRACTION16chain 'B' and (resid 138 through 155 )B138 - 155
17X-RAY DIFFRACTION17chain 'B' and (resid 156 through 168 )B156 - 168

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