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- PDB-6kk3: Crystal structure of Zika NS2B-NS3 protease with compound 4 -

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Basic information

Entry
Database: PDB / ID: 6kk3
TitleCrystal structure of Zika NS2B-NS3 protease with compound 4
Components(Genome polyprotein) x 2
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-DUU / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 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: Genome polyprotein
B: Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,3773
Polymers20,7182
Non-polymers6591
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3990 Å2
ΔGint-26 kcal/mol
Surface area9360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.580, 42.580, 215.260
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-339-

HOH

21B-352-

HOH

31B-359-

HOH

41B-360-

HOH

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Components

#1: Protein/peptide Genome polyprotein


Mass: 4218.545 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 Genome polyprotein


Mass: 16499.791 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Gene: GP1, A2G93_63394gpGP1 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A142IX72, UniProt: Q32ZE1*PLUS
#3: Chemical ChemComp-DUU / 1-[(10~{R},17~{S},20~{S})-17,20-bis(4-azanylbutyl)-4,9,16,19,22-pentakis(oxidanylidene)-3,8,15,18,21-pentazabicyclo[22.2.2]octacosa-1(26),24,27-trien-10-yl]guanidine


Mass: 658.835 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H54N10O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / 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: 2.34 Å3/Da / Density % sol: 47.44 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.2M Ammonium Sulfate, 0.1M Sodium Acetate Trihydrate pH 4.6, 30% Peg 2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: TPS 05A / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Nov 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→53.815 Å / Num. obs: 13375 / % possible obs: 99.9 % / Redundancy: 12 % / CC1/2: 1 / Rmerge(I) obs: 0.155 / Net I/σ(I): 10.6
Reflection shellResolution: 2.05→2.12 Å / Redundancy: 12.4 % / Rmerge(I) obs: 1.436 / Num. unique obs: 1289 / CC1/2: 0.72 / % possible all: 100

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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: 2.05→53.815 Å / Cross valid method: NONE
RfactorNum. reflection% reflection
Rfree0.2173 673 -
Rwork0.1894 --
obs-13375 99.9 %
Displacement parametersBiso max: 97.02 Å2 / Biso min: 19.08 Å2
Refinement stepCycle: final / Resolution: 2.05→53.815 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1419 0 101 76 1596
Biso mean--57.18 44.58 -
Num. residues----192
LS refinement shellResolution: 2.05→2.12 Å /
RfactorNum. reflection
Rfree0.351 -
Rwork0.257 1289
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)
12.20431.4571.28325.10212.30775.72050.24290.03420.5272-0.119-0.49410.284-0.4961-0.450.03510.3070.07570.07240.31180.05860.374-26.32169.7102-18.7244
23.48030.3083-0.69372.4321.15143.85960.0383-0.0455-0.1601-0.2330.0893-0.2599-0.14830.5284-0.08610.29430.04680.05520.27390.01210.2703-8.4923-5.5276-19.1947
33.68611.87170.0143.9246-0.0812.45310.24980.42130.6220.171-0.02970.442-0.3083-0.3686-0.24940.3230.07870.03210.28770.03820.2882-26.99858.9444-17.6878
42.11421.9738-0.84881.9381-1.53332.33680.2831-0.05480.44070.3-0.03370.3632-0.4832-0.1133-0.15530.33090.04240.09640.2373-0.01940.3452-23.17148.6333-10.0722
51.2876-0.2925-0.56720.86551.05791.9922-0.0119-0.0459-0.10360.1458-0.06080.04070.3229-0.04270.05490.27840.02690.04480.21830.03590.2531-20.6873-5.7297-12.6685
60.5486-0.6082-0.19252.96660.20170.09120.10460.170.0926-0.4612-0.1533-0.13990.00820.07880.14640.32060.06480.010.25830.04420.25-17.41212.6943-27.3695
71.774-0.26160.29462.4096-0.95454.129-0.3254-0.4155-0.37370.29270.0528-0.33250.43890.09620.15950.31510.08330.06930.33810.06670.3457-7.9183-12.359-14.8393
81.89760.16340.26511.7860.96061.6816-0.14040.0145-0.0796-0.33380.03870.0331-0.06460.02740.11950.27010.06440.01750.26420.04770.2416-16.5931-1.002-22.3098
93.30430.11051.32662.51351.1313.26630.1970.11790.1174-0.0499-0.0402-0.0051-0.26330.3429-0.1470.22750.01290.05780.23870.00740.2021-11.1163-2.9034-16.6364
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 170 )B146 - 170

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