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- PDB-7zum: Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus i... -

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Basic information

Entry
Database: PDB / ID: 7zum
TitleCrystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2130
Components
  • Serine protease NS3
  • Serine protease subunit NS2B
KeywordsVIRAL PROTEIN / FLAVIVIRIN / SERINE PROTEASE / NS2B-NS3 / ZIKA VIRUS
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 / 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 / protein-macromolecule adaptor 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 / 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 / protein-macromolecule adaptor activity / symbiont-mediated suppression of host toll-like receptor signaling pathway / clathrin-dependent endocytosis of virus by host cell / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / 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 / 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 / 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
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 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 / 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 / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-JN9 / Genome polyprotein
Similarity search - Component
Biological speciesZika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsHuber, S. / Steinmetzer, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Arch Pharm / Year: 2024
Title: Synthesis and structural characterization of new macrocyclic inhibitors of the Zika virus NS2B-NS3 protease.
Authors: Huber, S. / Braun, N.J. / Schmacke, L.C. / Murra, R. / Bender, D. / Hildt, E. / Heine, A. / Steinmetzer, T.
History
DepositionMay 12, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Jun 12, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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: Serine protease NS3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6883
Polymers24,9032
Non-polymers7851
Water2,108117
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3970 Å2
ΔGint-24 kcal/mol
Surface area9000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.343, 60.623, 80.889
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
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 / Flavivirin protease NS2B regulatory subunit / Non-structural protein 2B


Mass: 5865.384 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Plasmid: bZiPro / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q32ZE1
#2: Protein Serine protease NS3 / Flavivirin protease NS3 catalytic subunit / Non-structural protein 3


Mass: 19037.592 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Plasmid: bZiPro / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q32ZE1, flavivirin, nucleoside-triphosphate phosphatase, RNA helicase
#3: Chemical ChemComp-JN9 / 1-[(5R,8R,15S,18S)-15-(4-azanylbutyl)-5-(cyclohexylmethyl)-18-(1H-indol-3-ylmethyl)-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 / (2R,3S,4R,5R,6R)-6-((1R,2R,3S,4R,6S)-4,6-DIAMINO-2,3-DIHYDROXYCYCLOHEXYLOXY)-5-AMINO-2-(AMINOMETHYL)-TETRAHYDRO-2H-PYRA N-3,4-DIOL / NEOMYCIN A / NEAMINE / (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-alpha-D-glucoside / (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-D-glucoside / (1R,2R,3S,4R,6S)-4,6-diamino-2,3-dihydroxycyclohexyl 2,6-diamino-2,6-dideoxy-glucoside


Mass: 784.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H60N10O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 117 / 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: 2.43 Å3/Da / Density % sol: 49.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6 / Details: 0,1 M sodium acetate pH4.6 1,4 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.82656 Å
DetectorType: DECTRIS PILATUS3 S 2M / Detector: PIXEL / Date: Nov 28, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.82656 Å / Relative weight: 1
ReflectionResolution: 1.75→48.51 Å / Num. obs: 25151 / % possible obs: 99.8 % / Redundancy: 7.95 % / Biso Wilson estimate: 31.37 Å2 / CC1/2: 1 / Rsym value: 0.033 / Net I/σ(I): 30.22
Reflection shellResolution: 1.75→1.85 Å / Redundancy: 7.42 % / Mean I/σ(I) obs: 3.56 / Num. unique obs: 3972 / CC1/2: 0.968 / Rsym value: 0.461 / % possible all: 99.2

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5GPI

5gpi


Resolution: 1.75→24.61 Å / SU ML: 0.2039 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.3138
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2036 1256 5 %
Rwork0.1825 23846 -
obs0.1836 25102 99.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 48.25 Å2
Refinement stepCycle: LAST / Resolution: 1.75→24.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1403 0 57 117 1577
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00941492
X-RAY DIFFRACTIONf_angle_d1.00072033
X-RAY DIFFRACTIONf_chiral_restr0.0641227
X-RAY DIFFRACTIONf_plane_restr0.0065283
X-RAY DIFFRACTIONf_dihedral_angle_d14.8343881
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.820.32591360.25062566X-RAY DIFFRACTION98.15
1.82-1.90.32921380.22622623X-RAY DIFFRACTION99.78
1.9-20.23651370.20812585X-RAY DIFFRACTION99.89
2-2.130.23751380.19952620X-RAY DIFFRACTION99.86
2.13-2.290.23551390.19962639X-RAY DIFFRACTION99.89
2.29-2.520.27321400.20932661X-RAY DIFFRACTION99.79
2.52-2.890.25461400.20962670X-RAY DIFFRACTION99.96
2.89-3.630.22531400.18572674X-RAY DIFFRACTION100
3.63-24.610.13851480.15062808X-RAY DIFFRACTION99.73
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)
19.46340759899-3.203372893051.680954480522.76599656343-2.557702378032.736325459460.0873184612950.790142037294-1.13966602816-1.147892792690.257342267265-1.128283027811.13974412637-0.103712675371-0.1299908741790.611200687135-0.04195041844830.09256288057520.346712409213-0.08223247847650.541302305312-7.21853424572-32.13550716142.75083412678
26.384719527126.708050906895.346215792727.056657512885.713245170575.373608457780.0865772752396-0.376982488328-0.7252293414010.8928406476190.4930745296270.3973191028861.253680437840.00394471845144-0.2277815793690.4896608850380.04393601209180.0628170065770.3914200727850.1747633709920.431145370819-4.03260610556-30.010920443916.9549679726
32.001752155186.903661288134.169467144499.799400361376.775760349314.753377141830.83506874006-1.34892959193-0.7369716987960.794405402958-0.715287207849-0.818068094192-0.04943257936850.179630992087-0.1315774493030.610739316152-0.06597441280810.008768794498730.6010760910370.08516466829710.254890813384-1.57843811438-19.316743033826.0827949196
40.47775491129-1.443239811131.238959025064.35275359789-3.73771551943.208087405970.402369831088-1.35235537094-2.041737993750.475325779406-0.796180044844-0.4915418833750.3316730107930.6537006032370.503188173860.35820542553-0.170571457034-0.241391315930.7501264890170.5110656227191.017619504696.69777819751-12.426961629424.353166594
56.41223505471.524754233433.268686741395.42361300218-0.8619552939787.22637334457-0.1555590599890.2679866102991.00382328624-0.2226923055880.3969846748971.06102845155-0.608505506848-0.0242586602949-0.2662195110940.3374858457370.00672820589040.009311704129720.3189320993750.05000856311540.671635720151-4.89165504415-1.512015484415.32744671807
68.86907092330.263225993711-2.896374090269.338080111470.532963064932.53601519604-0.226558561607-0.303701912732-0.8666541753260.308499395424-0.13066661570.3056828886160.518296271618-0.0947389819580.4075568310940.258565081969-0.01387325178320.03012517648540.2506461881920.05355057800950.33805248035-7.14428363011-29.500344082611.5294264466
73.92727384683-1.09045318630.6420362902488.656166557021.779268711126.92323942264-0.0997644538016-0.0571098499091-0.494983848711-0.208868225201-0.107279742610.06989038157270.1305125612940.06830935070390.3233999554480.2427477072710.007542586705170.0009187321019930.2110981953330.02273971353530.291106882758-8.39462015699-24.41585114497.24859344735
87.9017777672-1.169842176311.183156850192.02264295583-3.597560411837.192042195850.0598694795363-0.00620898563784-0.427525973198-0.616577616568-0.05818489269090.5626389953080.617575180098-0.2073820068120.01619217458310.312218349298-0.0591277302616-0.06617015682150.279497031639-0.04039819454570.522222759942-16.0723623951-27.30061438484.6169175529
91.27086546599-0.3583004419530.1103689771713.22940592367-4.558285883996.57735240288-0.2681178966950.0511921676310.927649305296-0.3814620892370.4214269912111.66132224086-0.0994228764802-0.0945533038029-0.2745957097940.2689771764110.0311478672712-0.0753844332360.2908888876550.03064230900290.596461714799-14.6829304349-16.00086697035.1069791967
102.033889846150.8751161477360.4122525595135.765444830571.594658205382.886814173260.215787556867-0.9033227485550.4029440900450.61403324856-0.1842466364210.379547878126-0.164486076277-0.1652527354640.006371667812950.331984802144-0.02433660476390.08225534184070.360953504856-0.003561300282270.262256099568-6.6496896618-15.873197979917.6265826243
113.548524032711.51129754596-0.2516920215096.53591953861-0.2862826648635.90142247425-0.054111850059-0.5706916944870.7862710552050.942167425939-0.0007940945229120.290225728309-0.462781267959-0.133921813109-0.1808931511270.295627631-0.007578465006350.0894637751120.349249846778-0.1021189521680.320069010933-1.41008260049-6.9668454121917.1025256751
123.044988684151.03756061211-1.032543059953.32767211664-0.3112040831993.403231903110.0885678871209-0.2840570665040.4599193843490.342340562586-0.05713646605160.471432457487-0.04608310193-0.06671760641920.004721668597190.2447747140040.02453046630990.03545053087220.269044772875-0.05608929272690.282527848279-4.28915552687-10.604860464712.4106870966
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 49 through 53 )
2X-RAY DIFFRACTION2chain 'A' and (resid 54 through 58 )
3X-RAY DIFFRACTION3chain 'A' and (resid 59 through 63 )
4X-RAY DIFFRACTION4chain 'A' and (resid 64 through 68 )
5X-RAY DIFFRACTION5chain 'A' and (resid 69 through 88 )
6X-RAY DIFFRACTION6chain 'B' and (resid 17 through 28 )
7X-RAY DIFFRACTION7chain 'B' and (resid 29 through 53 )
8X-RAY DIFFRACTION8chain 'B' and (resid 54 through 71 )
9X-RAY DIFFRACTION9chain 'B' and (resid 72 through 79 )
10X-RAY DIFFRACTION10chain 'B' and (resid 80 through 106 )
11X-RAY DIFFRACTION11chain 'B' and (resid 107 through 118 )
12X-RAY DIFFRACTION12chain 'B' and (resid 119 through 170 )

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