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- PDB-7vlh: Crystal structure of Zika NS2B-NS3 protease with compound MI2219 -

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Basic information

Entry
Database: PDB / ID: 7vlh
TitleCrystal structure of Zika NS2B-NS3 protease with compound MI2219
Components
  • NS3 protease
  • Serine protease subunit NS2B
KeywordsVIRAL PROTEIN / NS3 Protease
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 / 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 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 / 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 / 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 / molecular adaptor activity / 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 / symbiont-mediated suppression of host innate immune response / 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 / symbiont entry into host cell / 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-7Q3 / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.621 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
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)25,5974
Polymers24,9032
Non-polymers6942
Water543
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3920 Å2
ΔGint-36 kcal/mol
Surface area8530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.992, 40.992, 214.435
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-7Q3 / 1-[(3~{S},6~{R},18~{R})-3,6-bis(4-azanylbutyl)-2,5,8,11,14,17-hexakis(oxidanylidene)-1,4,7,10,13,16-hexazacyclodocos-18-yl]guanidine


Mass: 597.711 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H47N11O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.81 Å3/Da / Density % sol: 31.99 %
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: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.953726 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.953726 Å / Relative weight: 1
ReflectionResolution: 2.62→40.26 Å / Num. obs: 6110 / % possible obs: 99.44 % / Redundancy: 12.1 % / CC1/2: 0.999 / Net I/σ(I): 16.55
Reflection shellResolution: 2.62→2.715 Å / Redundancy: 12.1 % / Num. unique obs: 580 / CC1/2: 0.947 / % possible all: 98.3

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5GPI

5gpi


Resolution: 2.621→40.26 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / Phase error: 32.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2891 305 5.01 %
Rwork0.2387 5784 -
obs-6087 99.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 110.18 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 2.621→40.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1339 0 93 3 1435
Biso mean--83.33 61.52 -
Num. residues----191
LS refinement shellResolution: 2.621→3.715 Å / Rfactor Rfree: 0.3619 / Rfactor Rwork: 0.3474 / Rfactor Rfree error: 0
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)
15.37123.73282.40335.35422.43945.5826-0.3611-0.0347-0.0287-0.75540.08340.4049-0.4009-1.37330.09730.6127-0.1111-0.02330.77480.0250.4378-25.10059.1803-17.8451
25.51011.7867-0.01428.3284-7.16316.6194-0.1347-0.25361.66710.0843-0.02-0.03941.79931.31780.22920.8839-0.2128-0.06660.8345-0.11490.4188-22.0691-5.6444-31.9606
35.6927-2.87675.51397.3049-1.5145.75350.04182.00860.5021-2.10310.9691-1.707-1.37111.0212-0.59831.0183-0.2460.28151.281-0.17360.6717-6.1334-7.7118-26.9836
48.9997-3.9445-5.81997.82021.62154.0053-0.6943-0.98720.70760.52281.0545-0.53221.56860.064-0.84820.6495-0.0175-0.14780.8036-0.0560.6209-2.7352-5.8001-7.2183
53.79213.2478-1.7079.6957-3.97252.38710.1060.270.15040.44890.13210.23240.0868-0.2485-0.15960.5645-0.0544-0.01330.6708-0.02420.3622-21.71886.997-14.3517
62.0793-0.44620.44023.55190.23296.8617-0.3655-1.24421.43950.70390.40750.2699-1.0073-1.10010.07430.8582-0.03290.13220.7453-0.12460.7404-26.533110.8686-7.5499
72.9859-0.81890.26091.02120.45673.7907-0.1872-0.0981-0.04430.09810.1670.00810.3571-0.0498-0.00230.4095-0.1207-0.04050.4573-0.01220.4084-19.2142-3.1699-14.6088
85.5828-4.22222.64717.0168-3.98163.7584-0.6779-0.89320.7517-0.0550.3007-1.80950.0889-0.9760.20060.5117-0.1459-0.08040.6063-0.0730.5532-10.0692-8.5037-22.9093
96.3414-0.78152.11367.63951.21642.548-0.3123-0.6824-0.42760.84540.18010.08180.1910.85550.17570.3879-0.12780.06240.6199-0.00180.264-10.4335-3.1602-18.2215
106.69450.67562.6563.51050.83651.51710.16491.0747-0.43830.20160.0714-0.20650.02590.2366-0.24330.6153-0.09280.07660.6833-0.05460.4303-11.4881-4.5509-19.5569
119.29033.89282.84522.834-1.0987.82741.2347-1.7054-0.47841.4929-0.45381.30820.9624-0.7526-1.00480.4994-0.15010.04910.7526-0.03470.6524-17.2464-8.135-12.1123
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 50 through 59 )A50 - 59
2X-RAY DIFFRACTION2chain 'A' and (resid 60 through 64 )A60 - 64
3X-RAY DIFFRACTION3chain 'A' and (resid 65 through 74 )A65 - 74
4X-RAY DIFFRACTION4chain 'A' and (resid 75 through 87 )A75 - 87
5X-RAY DIFFRACTION5chain 'B' and (resid 18 through 53 )B18 - 53
6X-RAY DIFFRACTION6chain 'B' and (resid 54 through 66 )B54 - 66
7X-RAY DIFFRACTION7chain 'B' and (resid 67 through 106 )B67 - 106
8X-RAY DIFFRACTION8chain 'B' and (resid 107 through 118 )B107 - 118
9X-RAY DIFFRACTION9chain 'B' and (resid 119 through 139 )B119 - 139
10X-RAY DIFFRACTION10chain 'B' and (resid 140 through 163 )B140 - 163
11X-RAY DIFFRACTION11chain 'B' and (resid 164 through 170 )B164 - 170

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