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- PDB-6mo0: Structure of dengue virus protease with an allosteric Inhibitor t... -

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Basic information

Entry
Database: PDB / ID: 6mo0
TitleStructure of dengue virus protease with an allosteric Inhibitor that blocks replication
ComponentsFLAVIVIRUS_NS2B/Peptidase S7
KeywordsVIRAL PROTEIN/INHIBITOR / Allosteric Inhibitor / Inhibitor / Complex / Protease / VIRAL PROTEIN / VIRAL PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / double-stranded RNA binding / channel activity / viral capsid / monoatomic ion transmembrane transport / clathrin-dependent endocytosis of virus by host cell ...symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / double-stranded RNA binding / channel activity / viral capsid / monoatomic ion transmembrane transport / clathrin-dependent endocytosis of virus by host cell / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / protein dimerization activity / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / 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 / viral envelope / host cell nucleus / virion attachment to host cell / structural molecule activity / virion membrane / proteolysis / extracellular region / ATP binding / membrane / metal ion binding
Similarity search - Function
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 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 / 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, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-JVJ / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesDengue virus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsLin, Y.-L. / Nie, S. / Hua, Y. / Wu, J. / Wu, F. / Huo, T. / Yao, Y. / Song, Y.
Funding support United States, 1items
OrganizationGrant numberCountry
Other governmentW81XWH-18-1-0368 United States
CitationJournal: J. Am. Chem. Soc. / Year: 2019
Title: Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease.
Authors: Yao, Y. / Huo, T. / Lin, Y.L. / Nie, S. / Wu, F. / Hua, Y. / Wu, J. / Kneubehl, A.R. / Vogt, M.B. / Rico-Hesse, R. / Song, Y.
History
DepositionOct 3, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 11, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: FLAVIVIRUS_NS2B/Peptidase S7
B: FLAVIVIRUS_NS2B/Peptidase S7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,5424
Polymers52,6612
Non-polymers8812
Water00
1
A: FLAVIVIRUS_NS2B/Peptidase S7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,7712
Polymers26,3301
Non-polymers4411
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: FLAVIVIRUS_NS2B/Peptidase S7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,7712
Polymers26,3301
Non-polymers4411
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)109.108, 109.108, 75.848
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number150
Space group name H-MP321
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: MET / Beg label comp-ID: MET / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: _ / Auth seq-ID: 48 - 1170 / Label seq-ID: 6 - 232

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein FLAVIVIRUS_NS2B/Peptidase S7


Mass: 26330.496 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Dengue virus 2 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A0B4L2Y4, UniProt: Q91H74
#2: Chemical ChemComp-JVJ / 1-(4-{3-[4-(furan-3-yl)phenyl]-5-[(piperidin-4-yl)methoxy]pyrazin-2-yl}phenyl)methanamine


Mass: 440.537 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H28N4O2

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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: 2.48 Å3/Da / Density % sol: 50.36 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / Details: 35% PEG 200, 100 mM MES, pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS3 X 6M / Detector: PIXEL / Date: Jun 25, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 14589 / % possible obs: 100 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.395 / Net I/σ(I): 15.29
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 8.8 % / Rmerge(I) obs: 2.036 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 1435 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2FOM

2fom


Resolution: 2.7→40.13 Å / Cor.coef. Fo:Fc: 0.896 / Cor.coef. Fo:Fc free: 0.856 / SU B: 34.684 / SU ML: 0.319 / Cross valid method: THROUGHOUT / ESU R Free: 0.368 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31055 709 4.9 %RANDOM
Rwork0.25629 ---
obs0.25881 13865 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 52.418 Å2
Baniso -1Baniso -2Baniso -3
1--1.73 Å2-0.86 Å20 Å2
2---1.73 Å2-0 Å2
3---5.6 Å2
Refinement stepCycle: 1 / Resolution: 2.7→40.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2512 0 66 0 2578
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0132634
X-RAY DIFFRACTIONr_bond_other_d0.0180.0182492
X-RAY DIFFRACTIONr_angle_refined_deg1.4931.6783542
X-RAY DIFFRACTIONr_angle_other_deg1.7051.6195790
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0695322
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.223.103116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg30.28515460
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.7581512
X-RAY DIFFRACTIONr_chiral_restr0.060.2320
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022898
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02536
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it8.4655.1231306
X-RAY DIFFRACTIONr_mcbond_other8.4665.1221305
X-RAY DIFFRACTIONr_mcangle_it10.6237.6721622
X-RAY DIFFRACTIONr_mcangle_other10.6217.6711623
X-RAY DIFFRACTIONr_scbond_it7.8915.8841325
X-RAY DIFFRACTIONr_scbond_other7.8885.8831326
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other10.0788.4571919
X-RAY DIFFRACTIONr_long_range_B_refined10.84996.73310099
X-RAY DIFFRACTIONr_long_range_B_other10.8596.73510097
X-RAY DIFFRACTIONr_rigid_bond_restr6.55435119
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 4203 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.23 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.703→2.773 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 65 -
Rwork0.322 971 -
obs--97.74 %

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