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- PDB-6kk2: Crystal structure of Zika NS2B-NS3 protease with compound 2 -

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Basic information

Entry
Database: PDB / ID: 6kk2
TitleCrystal structure of Zika NS2B-NS3 protease with compound 2
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-D9U / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.02 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
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)25,5623
Polymers24,9032
Non-polymers6591
Water68538
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4100 Å2
ΔGint-26 kcal/mol
Surface area9220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.413, 42.413, 215.689
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-323-

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
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-D9U / 1-[(10~{S},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(27),24(28),25-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.: 38 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.95 Å3/Da / Density % sol: 36.84 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop
Details: 0.2M Ammonium Sulfate, 0.1M Sodium acetate trihydrate 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: 0.95372 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 2, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95372 Å / Relative weight: 1
ReflectionResolution: 2.02→42.4 Å / Num. obs: 13825 / % possible obs: 99.4 % / Redundancy: 13.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.196 / Net I/σ(I): 35.1
Reflection shellResolution: 2.02→2.1 Å / Redundancy: 12.8 % / Rmerge(I) obs: 0.593 / Mean I/σ(I) obs: 3 / Num. unique obs: 1265 / CC1/2: 0.96 / % possible all: 95.2

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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: 2.02→42.4 Å / Cross valid method: NONE
RfactorNum. reflection% reflection
Rfree0.256 689 5.01 %
Rwork0.219 --
obs-13825 99.4 %
Displacement parametersBiso max: 101.88 Å2 / Biso min: 24.22 Å2
Refinement stepCycle: final / Resolution: 2.02→42.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1431 0 47 38 1516
Biso mean--65.22 49.21 -
Num. residues----193
LS refinement shellResolution: 2.02→2.09 Å /
RfactorNum. reflection
Rfree0.298 61
Rwork0.235 -
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)
14.67860.4840.58388.60093.557.58350.44460.503-0.00340.5306-0.61130.5770.0765-1.2497-0.2060.36540.0458-0.01960.41220.020.3471-26.35069.8197-18.6458
22.38610.24140.71.82750.40622.4380.07730.06770.1458-0.6183-0.097-0.35040.08610.6056-0.01490.65070.09360.11050.5829-0.09520.4215-8.6585-5.5092-19.1788
33.715-0.21111.81912.76091.44293.9284-0.05660.06390.8887-0.436-0.22670.86120.1585-0.8072-0.02130.5748-0.066-0.01430.37970.03370.3513-27.30259.1963-17.7159
43.50782.1215-0.64764.196-0.39261.96770.4675-0.16620.52280.1059-0.47970.5048-0.1403-0.29-0.12040.4137-0.00960.0120.253-0.02290.3617-20.402913.4744-15.3792
53.2324-0.2661-0.38772.12290.48912.5464-0.27940.1320.3689-0.02670.30760.1519-0.6137-0.1358-0.08570.3653-0.01560.05050.27920.02210.3461-23.48167.2599-9.3768
63.85850.1976-0.19061.6808-0.11672.68970.46060.3627-0.15190.4616-0.13360.1198-0.31560.0213-0.06280.4487-0.02740.06130.2312-0.00660.3258-22.57542.8378-4.653
71.21920.1816-0.78011.63010.13092.3933-0.2750.6781-0.25380.1477-0.43230.32241.0155-0.42110.14040.4783-0.0359-0.00270.3151-0.01290.352-22.2432-9.0408-16.4069
83.07070.5282-0.89254.82960.4552.71410.37860.98240.3417-0.4883-0.3957-0.4224-0.0564-0.3296-0.11830.36270.04040.02350.34950.0470.391-18.35915.3151-26.4824
91.77220.5285-0.07931.35710.97840.6373-0.04020.292-0.1139-0.1051-0.00480.0879-0.13260.05920.02540.3513-0.02170.0480.3926-0.02740.3253-10.9629-4.4839-20.1229
104.0803-0.59340.28612.6921.44283.74980.1687-0.24710.1014-0.36760.0240.0042-0.07420.2585-0.17610.406-0.05530.05990.247-0.00670.3018-14.7877-4.2829-17.8777
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 42 )B28 - 42
5X-RAY DIFFRACTION5chain 'B' and (resid 43 through 62 )B43 - 62
6X-RAY DIFFRACTION6chain 'B' and (resid 63 through 79 )B63 - 79
7X-RAY DIFFRACTION7chain 'B' and (resid 80 through 94 )B80 - 94
8X-RAY DIFFRACTION8chain 'B' and (resid 95 through 106 )B95 - 106
9X-RAY DIFFRACTION9chain 'B' and (resid 107 through 137 )B107 - 137
10X-RAY DIFFRACTION10chain 'B' and (resid 138 through 171 )B138 - 171

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