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- PDB-6kk4: Crystal structure of Zika NS2B-NS3 protease with compound 9 -

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Basic information

Entry
Database: PDB / ID: 6kk4
TitleCrystal structure of Zika NS2B-NS3 protease with compound 9
Components
  • NS3 protease
  • Serine protease subunit NS2B
KeywordsVIRAL PROTEIN / Viral protease / Protease inhibitor complex
Function / homology
Function and homology information


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 / double-stranded RNA binding / nucleoside-triphosphate phosphatase / viral capsid / 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 ...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 / double-stranded RNA binding / nucleoside-triphosphate phosphatase / viral capsid / 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 perinuclear region of cytoplasm / protein dimerization activity / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated suppression of host innate immune response / induction by virus of host autophagy / symbiont entry into host cell / 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 / lipid binding / viral envelope / 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
Thrombin, subunit H - #120 / Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / : / mRNA cap 0/1 methyltransferase / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C ...Thrombin, subunit H - #120 / Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / : / mRNA cap 0/1 methyltransferase / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus NS2B domain profile. / Flavivirus non-structural protein NS2A / Flavivirus non-structural protein NS2A / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / 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 / Envelope glycoprotein M superfamily, flavivirus / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flavivirus envelope glycoprotein M / Flavivirus envelope glycoprotein E, stem/anchor domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation domain / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / : / Flavivirus NS3 helicase, C-terminal helical domain / Flavivirus glycoprotein, immunoglobulin-like 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 / Trypsin-like serine proteases / 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 / Thrombin, subunit H / 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 / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-DE0 / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.74 Å
AuthorsQuek, J.P.
Funding support Singapore, 3items
OrganizationGrant numberCountry
Other governmentStart up grant Singapore
Other governmentCBRG15May045 Singapore
Other governmentNRF2016NRF-CRP001-063 Singapore
CitationJournal: Chemmedchem / Year: 2020
Title: Structure-Based Macrocyclization of Substrate Analogue NS2B-NS3 Protease Inhibitors of Zika, West Nile and Dengue viruses.
Authors: Braun, N.J. / Quek, J.P. / Huber, S. / Kouretova, J. / Rogge, D. / Lang-Henkel, H. / Cheong, E.Z.K. / Chew, B.L.A. / Heine, A. / Luo, D. / Steinmetzer, T.
History
DepositionJul 23, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 17, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 19, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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: NS3 protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6404
Polymers24,9032
Non-polymers7372
Water2,576143
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4280 Å2
ΔGint-25 kcal/mol
Surface area10080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.828, 60.432, 83.196
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
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 / 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, UniProt: Q32ZE1*PLUS
#3: Chemical ChemComp-DE0 / 1-[(9~{R},16~{S},19~{S})-16,19-bis(4-azanylbutyl)-4,8,15,18,21-pentakis(oxidanylidene)-3,7,14,17,20-pentazabicyclo[21.3.1]heptacosa-1(26),23(27),24-trien-9-yl]guanidine


Mass: 644.809 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H52N10O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 143 / 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: 2.46 Å3/Da / Density % sol: 50.09 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.2M Ammonium Sulfate, 0.1M Sodium Acetate Trihydrate pH 4.6, 25% Peg 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.95373 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95373 Å / Relative weight: 1
ReflectionResolution: 1.74→41.6 Å / Num. obs: 25939 / % possible obs: 99.7 % / Redundancy: 11.2 % / CC1/2: 1 / Rmerge(I) obs: 0.044 / Net I/σ(I): 36
Reflection shellResolution: 1.74→1.8 Å / Redundancy: 11 % / Rmerge(I) obs: 0.336 / Num. unique obs: 2483 / CC1/2: 0.96 / % possible all: 97.4

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5GPI

5gpi


Resolution: 1.74→41.6 Å / Cross valid method: NONE / σ(F): 1.39
RfactorNum. reflection% reflection
Rfree0.1836 1297 5 %
Rwork0.1624 --
obs-25939 99.69 %
Displacement parametersBiso max: 79.41 Å2 / Biso min: 11.05 Å2
Refinement stepCycle: final / Resolution: 1.74→41.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1477 0 60 143 1680
Biso mean--24.39 40.04 -
Num. residues----200
LS refinement shellResolution: 1.74→1.8076 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.243 123 -
Rwork0.212 2644 -
obs--97 %
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)
13.8691-0.16730.72124.9461.90176.03310.04080.0678-0.4745-0.0526-0.019-0.00810.48470.1046-0.03720.2496-0.0163-0.03610.1650.03280.2932-4.236-30.2910.2877
23.21210.80032.075.5714-2.09372.60140.4358-1.3071-0.80371.3424-0.6419-0.46890.27060.56980.13890.4676-0.06-0.0970.34710.09270.24690.3831-18.375428.6439
34.88451.50613.12223.1993-0.53687.2515-0.06880.12170.13980.08320.0035-0.03-0.2810.24970.08310.13680.02920.02940.1091-0.01530.1530.199-3.84018.1291
46.29040.2811-0.80926.77491.09948.24220.17820.1851-0.61060.1259-0.14470.24820.8139-0.64310.03830.1777-0.0406-0.05250.13110.01960.2076-5.6023-29.876610.33
54.53440.92470.68484.21-1.20033.72850.09030.1109-0.3002-0.1119-0.05250.0190.40330.03250.04030.13120.0036-0.01660.0952-0.02570.1165-5.7008-24.61276.1557
63.92050.94621.01356.8954-0.17683.58430.14980.0156-0.273-0.0185-0.02050.22810.3096-0.2194-0.10420.1061-0.0091-0.02260.1611-0.00670.117-12.2576-23.0942.1664
75.84883.95515.13844.19755.05828.5816-0.0504-0.65150.21820.0627-0.35660.4641-0.1478-0.86220.51370.16090.04550.04140.21490.00190.1752-12.8257-13.290916.4769
83.9224-3.2525-4.24833.60245.2157.9329-0.3724-0.2808-0.11010.81950.3635-0.3170.66680.4846-0.10520.23430.0035-0.01830.17030.01810.18182.9459-21.016617.6896
92.10151.74630.39643.4311-0.27525.7401-0.0616-0.06540.10650.5198-0.1311-0.3861-0.13860.15230.23340.1479-0.00580.02270.1233-0.02170.11320.2671-7.986817.6414
101.88380.5672-0.74113.4979-0.20243.20690.0213-0.13870.01840.1561-0.01540.097-0.1095-0.0341-0.01570.10410.0059-0.01420.1298-0.01190.1054-0.5679-11.101712.5644
115.39091.11692.54580.23540.57611.3796-0.1987-0.42170.2548-0.0991-0.04430.5399-0.0018-1.00930.08540.234-0.05540.02970.6086-0.04850.4155-22.104-14.959810.0462
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 49 through 60 )A49 - 60
2X-RAY DIFFRACTION2chain 'A' and (resid 61 through 65 )A61 - 65
3X-RAY DIFFRACTION3chain 'A' and (resid 66 through 87 )A66 - 87
4X-RAY DIFFRACTION4chain 'B' and (resid 17 through 28 )B17 - 28
5X-RAY DIFFRACTION5chain 'B' and (resid 29 through 53 )B29 - 53
6X-RAY DIFFRACTION6chain 'B' and (resid 54 through 79 )B54 - 79
7X-RAY DIFFRACTION7chain 'B' and (resid 80 through 93 )B80 - 93
8X-RAY DIFFRACTION8chain 'B' and (resid 94 through 106 )B94 - 106
9X-RAY DIFFRACTION9chain 'B' and (resid 107 through 118 )B107 - 118
10X-RAY DIFFRACTION10chain 'B' and (resid 119 through 163 )B119 - 163
11X-RAY DIFFRACTION11chain 'B' and (resid 164 through 177 )B164 - 177

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