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

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Basic information

Entry
Database: PDB / ID: 7zwk
TitleCrystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2162
Components
  • (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-alpha-D-glucopyranoside
  • 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 / symbiont-mediated suppression of host toll-like receptor signaling pathway ...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 / symbiont-mediated suppression of host toll-like receptor signaling pathway / protein-macromolecule adaptor activity / 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: 2 Å
AuthorsHuber, S. / Steinmetzer, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2162
Authors: Huber, S. / Braun, N. / Steinmetzer, T.
History
DepositionMay 19, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 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

Downloads & links

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Assembly

Deposited unit
A: Serine protease subunit NS2B
B: Serine protease NS3
C: (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-alpha-D-glucopyranoside
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,7644
Polymers25,6683
Non-polymers961
Water1,874104
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4900 Å2
ΔGint-41 kcal/mol
Surface area8830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.268, 42.268, 216.244
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number95
Space group name H-MP4322
Space group name HallP4cw2c
Symmetry operation#1: x,y,z
#2: -y,x,z+3/4
#3: y,-x,z+1/4
#4: x,-y,-z+1/2
#5: -x,y,-z
#6: -x,-y,z+1/2
#7: y,x,-z+1/4
#8: -y,-x,-z+3/4
Components on special symmetry positions
IDModelComponents
11B-360-

HOH

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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 (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-alpha-D-glucopyranoside


Mass: 764.917 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#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.: 104 / 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: 1.88 Å3/Da / Density % sol: 34.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 0.1 M sodium acetate pH 4.6 0.2 M ammonium sulfate 22% PEG2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 S 2M / Detector: PIXEL / Date: Mar 11, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2→42.27 Å / Num. obs: 14227 / % possible obs: 99.9 % / Redundancy: 24.83 % / Biso Wilson estimate: 30.95 Å2 / CC1/2: 1 / Rsym value: 0.083 / Net I/σ(I): 29.88
Reflection shellResolution: 2→2.12 Å / Redundancy: 23.95 % / Mean I/σ(I) obs: 6.2 / Num. unique obs: 2222 / CC1/2: 0.974 / Rsym value: 0.577 / % 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: 2→36.47 Å / SU ML: 0.2071 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 22.5935
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2218 711 5 %
Rwork0.1748 13507 -
obs0.1771 14218 99.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 34.1 Å2
Refinement stepCycle: LAST / Resolution: 2→36.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1376 0 58 104 1538
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00551476
X-RAY DIFFRACTIONf_angle_d0.79532015
X-RAY DIFFRACTIONf_chiral_restr0.0548225
X-RAY DIFFRACTIONf_plane_restr0.0045271
X-RAY DIFFRACTIONf_dihedral_angle_d13.7113856
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.150.2761370.1922597X-RAY DIFFRACTION99.67
2.15-2.370.25391390.18112634X-RAY DIFFRACTION99.75
2.37-2.710.2471400.20782657X-RAY DIFFRACTION99.79
2.71-3.420.2531420.18592701X-RAY DIFFRACTION100
3.42-36.470.18171530.15622918X-RAY DIFFRACTION100
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)
15.943310313095.49914204499-5.820808971485.16671333247-5.412402486785.71109297053-0.241281835925-0.492707759323-0.9059291647-0.176206025715-0.72344396322-0.7816544470460.2487578868210.2771395804531.011137790470.4868114223970.0920392741507-0.01753077364010.3240645403140.02063437275280.39364075609524.4138569681-15.2048502281-13.3759132295
21.135316506520.106674839412-0.2048485999462.989543055580.6771037972660.1972261270660.06025774418990.404325669843-0.1483973900770.02323703981910.1090295449660.0188903623578-0.295341052156-0.111373025244-0.1789484396680.3190710665910.0886381794860.05479168962410.3735339242130.02106507646240.28272511299325.83473856260.0622248907887-28.0815237688
33.970355547810.339015310071-1.00548548822.41888042615-2.247973929972.40806127253-0.01235188004910.01545946855910.217599416965-0.2003337282670.02199894130320.251969067338-0.162131157754-0.367865448077-0.001863768341180.2540191411250.0361957005221-0.03716696983860.193640914004-0.03761778319660.2439818261725.277203018386.23371318736-16.2629361865
46.858626424253.20853757461-2.971424883676.10840905936-2.872618364055.65585911690.273913120878-0.643949276072-0.2044558372080.369701216939-0.302239014675-0.253395043180.1153574766830.7500307761730.02516734564440.2114483028150.07780382560240.005610621777030.264223264242-0.02931998692330.22132198269226.3508756543-8.9839965541-17.8905118868
54.271079669792.874205485760.2079288985563.53757684150.9831065858713.301404420090.04339757779580.0356004047932-0.200680666838-0.0935380870912-0.1303564675190.08056966785820.451735118539-0.03230579852690.03702412438710.2838501165750.0293306410271-0.02343041936290.2530213156680.03605745084930.22915927154920.288531925-12.7097769812-15.6894072709
62.191465791072.418610472270.03265601220732.864961504150.05560152809182.337405849520.2151518747230.00410609208988-0.2920954368520.127166439835-0.0574619213603-0.17534195993-0.0355555369680.0853928033412-0.1228230052180.2357887664920.0451323162533-0.02610725658090.2668476613660.00849659638820.18605025363221.9968942364-3.46227133119-10.2038853254
72.520776398720.2251511539531.880342996343.23694736923-0.1423537990592.163255293770.21959570511-0.284340344026-0.4083364162590.5341422818420.214960621099-0.1629616833230.5318331988320.165728715974-0.3710159484570.3207431692640.000436741192105-0.1007935649210.2851719715620.03155040399260.28659789299526.2281395413-7.85058286011-5.39033638621
87.21999423502-1.80113589475-1.379656921471.31005317046-0.1348690820141.322585997080.2359406062160.0276501765410.152637207232-0.0274427979058-0.148581520464-0.117344344393-0.128561992088-0.0627217874666-0.07162716319490.318237789430.0139341486929-0.04162322096430.308042735983-0.01609317883940.20537068169718.2350089267-0.293244058056-6.02597393345
97.74878432027-4.99534814515.987575443874.88177876187-4.685985747075.67904978343-0.2609417624860.164259374280.9459908326180.189846453594-0.236979330285-0.453244601655-0.9742259725370.2387375530120.4001415862250.3157755834520.04531799634630.03916913270060.258669854823-0.02424394415770.30427946313322.02375577549.26965029189-16.3600158168
101.07693252186-0.2259906359020.2231065484137.131104003-0.2152971687260.04883236110380.1096350546950.254048333823-0.077255997761-0.4541795965210.0860156568847-0.117169177083-0.0178719727478-0.0386269849334-0.1825921733410.2746628059850.0723765665994-0.02207821784250.266149067619-0.01690181530860.2641375525617.8246475354-4.56951770432-26.0603439279
112.65708717847-0.707456342764-0.5251893218083.34710593638-1.42439616691.447784891270.0746814505720.07552513348680.179913230229-0.153675742516-0.004833775901730.141847508566-0.179241079729-0.268934195193-0.07235819820220.2448352491790.0607981540507-0.04015384558490.264000017536-0.02055877241060.22366454292110.94441413484.65812192857-20.1214670967
127.78984228412-2.2058634592-0.5092025727314.76557866078-3.874423939194.066409548390.2218341684160.2715354197720.456934448359-0.376106686182-0.3562539947870.0806634390775-0.3128418258260.4273595357050.08740756239850.3093353774330.03527934917640.01234230282030.192919297630.008695167510780.28470235734823.33682110487.58957525538-23.1918810186
134.143636006451.07784096305-1.080397981074.26222618149-0.8702603886542.20126693285-0.07627214508780.05703471546720.0770310484902-0.06905750929930.03790467651770.250607848588-0.00317855783113-0.2827215584480.1079698097990.2155250437090.0570399371024-0.035568663330.239909105607-0.01370404583260.18970484921410.32803004743.17304113971-16.8202329292
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 50 through 54 )
2X-RAY DIFFRACTION2chain 'A' and (resid 55 through 64 )
3X-RAY DIFFRACTION3chain 'A' and (resid 65 through 87 )
4X-RAY DIFFRACTION4chain 'B' and (resid 18 through 27 )
5X-RAY DIFFRACTION5chain 'B' and (resid 28 through 42 )
6X-RAY DIFFRACTION6chain 'B' and (resid 43 through 53 )
7X-RAY DIFFRACTION7chain 'B' and (resid 54 through 71 )
8X-RAY DIFFRACTION8chain 'B' and (resid 72 through 79 )
9X-RAY DIFFRACTION9chain 'B' and (resid 80 through 94 )
10X-RAY DIFFRACTION10chain 'B' and (resid 95 through 106 )
11X-RAY DIFFRACTION11chain 'B' and (resid 107 through 137 )
12X-RAY DIFFRACTION12chain 'B' and (resid 138 through 145 )
13X-RAY DIFFRACTION13chain 'B' and (resid 146 through 170 )

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