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- PDB-6kk6: Crystal structure of Zika NS2B-NS3 protease with compound 16 -

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Basic information

Entry
Database: PDB / ID: 6kk6
TitleCrystal structure of Zika NS2B-NS3 protease with compound 16
Components
  • NS3 protease
  • Serine protease subunit NS2B
KeywordsVIRAL PROTEIN / Viral protease / Protease inhibitor complex
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 / 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 / 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
Thrombin, subunit H - #120 / 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 ...Thrombin, subunit H - #120 / 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 / Trypsin-like serine proteases / 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-DV0 / 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)25,7365
Polymers24,9032
Non-polymers8333
Water1,78399
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4490 Å2
ΔGint-37 kcal/mol
Surface area8890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.570, 60.651, 83.350
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

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Protein , 2 types, 2 molecules AB

#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

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Non-polymers , 4 types, 102 molecules

#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#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: Chemical ChemComp-DV0 / 1-[(5~{R},8~{R},15~{S},18~{S})-15,18-bis(4-azanylbutyl)-5-methyl-4,7,14,17,20-pentakis(oxidanylidene)-3,6,13,16,19-pentazabicyclo[20.3.1]hexacosa-1(25),22(26),23-trien-8-yl]guanidine


Mass: 644.809 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H52N10O5 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 50.1 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / Details: 2M Ammonium Sulfate, 5% Propanol

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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→42 Å / Num. obs: 25997 / % possible obs: 99.6 % / Redundancy: 11.2 % / CC1/2: 1 / Rmerge(I) obs: 0.073 / Net I/σ(I): 21.6
Reflection shellResolution: 1.74→1.8 Å / Redundancy: 11 % / Rmerge(I) obs: 0.912 / Num. unique obs: 2478 / CC1/2: 0.83 / % possible all: 96.2

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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→42 Å / Cross valid method: NONE / σ(F): 1.34
RfactorNum. reflection% reflection
Rfree0.181 1299 5 %
Rwork0.1724 --
obs-24698 99.47 %
Displacement parametersBiso max: 90.34 Å2 / Biso min: 14.34 Å2
Refinement stepCycle: final / Resolution: 1.74→42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1401 0 57 99 1557
Biso mean--29.35 43.18 -
Num. residues----190
LS refinement shellResolution: 1.74→1.8054 Å /
RfactorNum. reflection
Rfree0.255 121
Rwork0.225 2357
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)
12.2856-2.9811-0.62798.0195-0.15311.14780.13310.4005-0.3317-0.7509-0.1639-0.23080.5928-0.0442-0.21070.3322-0.0108-0.05250.2365-0.04810.3801-4.343-31.75534.4508
21.1562-2.6983-0.53797.40062.19191.1456-0.03370.4038-0.1814-0.011-0.42770.52680.4144-0.50740.32680.46180.01030.05490.34080.05180.2816-5.0587-27.978919.5001
36.0545.2712-3.01976.8945-5.64737.78290.1428-0.6234-0.36640.6229-0.4165-0.62170.10980.51170.3640.37330.0495-0.03360.276-0.05690.20872.8282-10.003622.2057
46.99685.97944.46335.93524.69843.9444-0.30410.54610.6053-0.66220.09320.8237-0.4387-0.15620.23560.291-0.0115-0.05540.26840.03020.2531-4.115-2.77661.034
57.2451-2.4451-4.11982.38712.96598.6403-0.10330.0433-0.78380.2318-0.07790.28690.7809-0.6577-0.03320.285-0.0258-0.00930.23940.02390.2765-5.8691-28.910211.9138
65.68350.82430.83285.5959-0.86795.95580.040.108-0.5095-0.2628-0.01490.11850.41350.08570.05780.17720.0096-0.01290.1304-0.02780.1706-5.8514-24.99736.5034
77.2784-1.62531.21866.4932-1.34985.89590.2618-0.0486-0.9617-0.2887-0.02190.66820.4318-0.3029-0.16920.1956-0.0226-0.07410.2492-0.04920.3184-13.694-26.69962.7035
81.81530.75771.36023.7061.473.04280.0064-0.23570.02620.2889-0.10880.5043-0.0279-0.33410.12240.18970.04420.04660.243-0.01150.2858-12.1259-13.574912.4891
94.7784-4.4289-5.37955.06456.86759.8999-0.3032-0.2601-0.07720.46510.3131-0.2960.33460.3644-0.05310.25230.0121-0.01750.22330.01040.19652.8692-20.942516.7295
103.25432.57811.47385.086-3.49488.0361-0.1748-0.08640.25540.2924-0.2204-0.6559-0.0040.23540.28050.22170.05170.03070.1958-0.04540.1308-0.2012-7.171317.1399
112.5266-0.1914-0.71925.405-0.07393.9187-0.0754-0.18130.08250.39120.03690.3444-0.159-0.16910.01020.14610.0119-0.01170.1868-0.02230.1417-3.1202-11.4814.4427
127.69122.8978-4.46715.4864-1.24825.0610.0107-0.08030.24390.06850.04310.0609-0.12670.0973-0.03810.16620.0146-0.01150.1572-0.01750.1244-0.6182-9.1879.7567
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 74 )A60 - 74
4X-RAY DIFFRACTION4chain 'A' and (resid 75 through 87 )A75 - 87
5X-RAY DIFFRACTION5chain 'B' and (resid 18 through 27 )B18 - 27
6X-RAY DIFFRACTION6chain 'B' and (resid 28 through 53 )B28 - 53
7X-RAY DIFFRACTION7chain 'B' and (resid 54 through 71 )B54 - 71
8X-RAY DIFFRACTION8chain 'B' and (resid 72 through 94 )B72 - 94
9X-RAY DIFFRACTION9chain 'B' and (resid 95 through 106 )B95 - 106
10X-RAY DIFFRACTION10chain 'B' and (resid 107 through 118 )B107 - 118
11X-RAY DIFFRACTION11chain 'B' and (resid 119 through 145 )B119 - 145
12X-RAY DIFFRACTION12chain 'B' and (resid 146 through 169 )B146 - 169

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