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- PDB-6kk5: Crystal structure of Zika NS2B-NS3 protease with compound 15 -

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Basic information

Entry
Database: PDB / ID: 6kk5
TitleCrystal structure of Zika NS2B-NS3 protease with compound 15
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 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 / double-stranded RNA binding / viral capsid / 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 / double-stranded RNA binding / viral capsid / 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 perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / protein dimerization activity / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / symbiont entry into host cell / induction by virus of host autophagy / RNA-directed RNA polymerase / virus-mediated perturbation of host defense response / 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 / 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
Thrombin, subunit H - #120 / : / Flavivirus capsid protein C superfamily / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus envelope glycoprotein E, stem/anchor domain / Flavivirus non-structural protein NS2B / : / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus ...Thrombin, subunit H - #120 / : / Flavivirus capsid protein C superfamily / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus envelope glycoprotein E, stem/anchor 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. / 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 / Flavivirus envelope glycoprotein M / 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 / 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-DE6 / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 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)25,5483
Polymers24,9032
Non-polymers6451
Water91951
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4120 Å2
ΔGint-27 kcal/mol
Surface area9070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.528, 42.528, 215.371
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number95
Space group name H-MP4322
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-322-

HOH

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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
Details: SF file contains Friedel pairs. / 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
Details: SF file contains Friedel pairs. / 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-DE6 / 1-[(5~{S},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
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 51 / 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: 1.96 Å3/Da / Density % sol: 37.09 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop
Details: 2M Ammonium Sulfate, 0.1M Sodium Acetate Trihydrate pH 4.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.97924 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Feb 23, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97924 Å / Relative weight: 1
ReflectionResolution: 2.03→42.528 Å / Num. obs: 13722 / % possible obs: 99.8 % / Redundancy: 12.4 % / CC1/2: 1 / Rmerge(I) obs: 0.091 / Net I/σ(I): 18.5
Reflection shellResolution: 2.03→2.1 Å / Redundancy: 12.7 % / Rmerge(I) obs: 1.37 / Num. unique obs: 1317 / CC1/2: 0.86 / % possible all: 99.5

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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: 2.03→42.528 Å / Cross valid method: NONE
RfactorNum. reflection% reflection
Rfree0.231 684 4.99 %
Rwork0.198 --
obs-13700 99.85 %
Displacement parametersBiso max: 99.99 Å2 / Biso min: 26.93 Å2
Refinement stepCycle: final / Resolution: 2.03→42.528 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1414 0 46 51 1511
Biso mean--49.21 50.15 -
Num. residues----191
LS refinement shellResolution: 2.03→2.1 Å / Rfactor Rfree error: 0 /
RfactorNum. reflection
Rfree0.308 68
Rwork0.274 -
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)
10.35240.09650.20020.2842-0.18480.22190.17350.15860.3621-0.3328-0.21030.5025-0.4224-0.31180.00210.62950.17950.09550.40470.05660.4567-26.46719.8887-18.6682
22.39920.4163-0.55521.84920.10.40540.09890.2182-0.0572-0.3653-0.1967-0.39430.0040.33460.00270.44750.15170.06290.53330.03850.3947-8.472-5.3893-19.1124
30.1083-0.01580.02230.445-0.37950.34410.16240.07850.5393-0.1207-0.28760.6457-0.4226-0.4209-0.00150.43290.15450.07180.37090.05440.4037-27.14929.144-17.6165
41.63311.1137-0.26411.1229-1.27662.2030.26910.0680.31570.3204-0.17930.1506-0.3215-0.12410.00270.39310.0810.09850.2948-0.00590.3944-23.29688.8236-10.0243
50.47730.6370.55951.6440.50350.4390.2452-0.0912-0.1096-0.2166-0.013-0.10860.25740.141-0.00060.45580.10150.01420.31660.00930.3483-20.7799-5.5327-12.6638
60.6910.2247-0.32150.1485-0.18130.31830.24450.29270.2773-1.0045-0.26170.24390.0725-0.11290.0040.46030.20810.04120.4610.08440.3925-17.79473.2622-27.6177
70.38230.1211-0.08710.35870.02240.02080.1711-0.1182-0.28420.2545-0.087-0.64620.23010.04380.00240.45570.15680.02370.49220.0740.4436-8.0677-12.2071-14.9311
80.853-0.04410.08730.2574-0.28030.57230.0180.23620.1321-0.9-0.38330.1376-0.15090.0827-0.01250.40790.18660.07340.41740.08050.3565-16.7681-0.7837-22.2798
90.9374-0.46520.15730.57580.4161.69940.20510.440.243-0.3203-0.1244-0.0366-0.33160.3562-0.02030.3540.10050.13890.41090.09180.3218-10.0628-2.3222-17.2022
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 50 through 60 )A50 - 60
2X-RAY DIFFRACTION2chain 'A' and (resid 61 through 87 )A61 - 87
3X-RAY DIFFRACTION3chain 'B' and (resid 17 through 27 )B17 - 27
4X-RAY DIFFRACTION4chain 'B' and (resid 28 through 71 )B28 - 71
5X-RAY DIFFRACTION5chain 'B' and (resid 72 through 94 )B72 - 94
6X-RAY DIFFRACTION6chain 'B' and (resid 95 through 111 )B95 - 111
7X-RAY DIFFRACTION7chain 'B' and (resid 112 through 125 )B112 - 125
8X-RAY DIFFRACTION8chain 'B' and (resid 126 through 145 )B126 - 145
9X-RAY DIFFRACTION9chain 'B' and (resid 146 through 169 )B146 - 169

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