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- PDB-4p1u: Influenza A (flu) virus polymerase basic protein 2 (PB2) bound to... -

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Basic information

Entry
Database: PDB / ID: 4p1u
TitleInfluenza A (flu) virus polymerase basic protein 2 (PB2) bound to VX787, an azaindole inhibitor
ComponentsPolymerase basic protein 2
Keywordstransferase/transferase inhibitor / small-molecule drug / inhibitor / flu / m7-GTP pocket / transferase-transferase inhibitor complex
Function / homology
Function and homology information


cap snatching / symbiont-mediated suppression of host mRNA transcription via inhibition of RNA polymerase II activity / host cell mitochondrion / 7-methylguanosine mRNA capping / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / virion component / viral RNA genome replication / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / DNA-templated transcription ...cap snatching / symbiont-mediated suppression of host mRNA transcription via inhibition of RNA polymerase II activity / host cell mitochondrion / 7-methylguanosine mRNA capping / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / virion component / viral RNA genome replication / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / DNA-templated transcription / host cell nucleus / RNA binding
Similarity search - Function
Influenza RNA-dependent RNA polymerase subunit PB2 / PB2, C-terminal / : / : / : / : / : / Influenza RNA polymerase PB2 N-terminal region / Influenza RNA polymerase PB2 second domain / Influenza RNA polymerase PB2 middle domain ...Influenza RNA-dependent RNA polymerase subunit PB2 / PB2, C-terminal / : / : / : / : / : / Influenza RNA polymerase PB2 N-terminal region / Influenza RNA polymerase PB2 second domain / Influenza RNA polymerase PB2 middle domain / Influenza RNA polymerase PB2 6th domain / Influenza RNA polymerase PB2 C-terminal domain / : / Influenza RNA polymerase PB2 CAP binding domain / : / Influenza RNA polymerase PB2 helical domain
Similarity search - Domain/homology
Chem-21G / Polymerase basic protein 2
Similarity search - Component
Biological speciesInfluenza A virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.52 Å
AuthorsJacobs, M.D.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2.
Authors: Clark, M.P. / Ledeboer, M.W. / Davies, I. / Byrn, R.A. / Jones, S.M. / Perola, E. / Tsai, A. / Jacobs, M. / Nti-Addae, K. / Bandarage, U.K. / Boyd, M.J. / Bethiel, R.S. / Court, J.J. / Deng, ...Authors: Clark, M.P. / Ledeboer, M.W. / Davies, I. / Byrn, R.A. / Jones, S.M. / Perola, E. / Tsai, A. / Jacobs, M. / Nti-Addae, K. / Bandarage, U.K. / Boyd, M.J. / Bethiel, R.S. / Court, J.J. / Deng, H. / Duffy, J.P. / Dorsch, W.A. / Farmer, L.J. / Gao, H. / Gu, W. / Jackson, K. / Jacobs, D.H. / Kennedy, J.M. / Ledford, B. / Liang, J. / Maltais, F. / Murcko, M. / Wang, T. / Wannamaker, M.W. / Bennett, H.B. / Leeman, J.R. / McNeil, C. / Taylor, W.P. / Memmott, C. / Jiang, M. / Rijnbrand, R. / Bral, C. / Germann, U. / Nezami, A. / Zhang, Y. / Salituro, F.G. / Bennani, Y.L. / Charifson, P.S.
History
DepositionFeb 27, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 30, 2014Provider: repository / Type: Initial release
Revision 1.1Aug 6, 2014Group: Database references
Revision 1.2Oct 1, 2014Group: Database references
Revision 1.3Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_oper_list / refine_hist
Item: _chem_comp.pdbx_synonyms / _citation.journal_id_CSD ..._chem_comp.pdbx_synonyms / _citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Polymerase basic protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,5742
Polymers19,1741
Non-polymers3991
Water84747
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area8560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.174, 81.174, 54.427
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65

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Components

#1: Protein Polymerase basic protein 2 / RNA-directed RNA polymerase subunit P3


Mass: 19174.324 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus / Strain: A/Victoria/3/1975 H3N2 / Gene: PB2 / Plasmid: pET28b.1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)pLysS / References: UniProt: P31345
#2: Chemical ChemComp-21G / (2S,3S)-3-[[5-fluoranyl-2-(5-fluoranyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic acid / 3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic acid / VX787 / (2S,3S)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid


Mass: 399.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19F2N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / Source method: isolated from a natural source / Formula: H2O

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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: 2.9 Å3/Da / Density % sol: 57.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.7
Details: 1 ?L protein solution (2.8 mg/ml protein, 50 mM Tris buffer pH 8, 200 mM sodium chloride, 2 mM dithiothreitol, 1 mM anthraquinone-2,6-disulfonic acid disodium salt, 7.5 mM GTP) and 0.4 ?L ...Details: 1 ?L protein solution (2.8 mg/ml protein, 50 mM Tris buffer pH 8, 200 mM sodium chloride, 2 mM dithiothreitol, 1 mM anthraquinone-2,6-disulfonic acid disodium salt, 7.5 mM GTP) and 0.4 ?L well solution (1.5 M sodium formate, 100 mM sodium citrate buffer pH 4.7, 10 mM dithiothreitol) was suspended over 1 mL of well solution. The crystals were transferred to a soaking solution (3.25 M sodium formate, 100 mM sodium citrate buffer pH 4.7) containing 1 mM VRT-0928787. Crystals were incubated approximately 15 hours t room temperature, and then transferred to a cryo-preservative solution (soaking solution with 25 % v/v glycerol) prior to freezing in liquid nitrogen.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 30, 2010
RadiationMonochromator: 0.9774 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.52→26.57 Å / Num. obs: 13202 / % possible obs: 97.3 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.045 / Net I/σ(I): 22.8
Reflection shellResolution: 2.52→2.8 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.388 / Mean I/σ(I) obs: 3.4 / % possible all: 98.8

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Processing

Software
NameVersionClassification
BUSTERrefinement
PDB_EXTRACT3.14data extraction
REFMAC5.5.0109refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.52→25.38 Å / Cor.coef. Fo:Fc: 0.9462 / Cor.coef. Fo:Fc free: 0.9169 / SU R Cruickshank DPI: 0.388 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.389 / SU Rfree Blow DPI: 0.261 / SU Rfree Cruickshank DPI: 0.264 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2426 343 4.91 %RANDOM
Rwork0.1776 ---
obs0.1808 6992 99.87 %-
Displacement parametersBiso max: 154.99 Å2 / Biso mean: 56.94 Å2 / Biso min: 27.29 Å2
Baniso -1Baniso -2Baniso -3
1-0.3572 Å20 Å20 Å2
2--0.3572 Å20 Å2
3----0.7145 Å2
Refine analyzeLuzzati coordinate error obs: 0.335 Å
Refinement stepCycle: final / Resolution: 2.52→25.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1236 0 29 47 1312
Biso mean--36.66 57.78 -
Num. residues----158
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d469SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes29HARMONIC2
X-RAY DIFFRACTIONt_gen_planes187HARMONIC5
X-RAY DIFFRACTIONt_it1290HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion169SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1497SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1290HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1734HARMONIC21.24
X-RAY DIFFRACTIONt_omega_torsion3.21
X-RAY DIFFRACTIONt_other_torsion18.97
LS refinement shellResolution: 2.52→2.82 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.3018 101 5.13 %
Rwork0.1916 1866 -
all0.1972 1967 -
obs--99.87 %
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)
11.5367-0.0963-0.37764.59692.74523.2168-0.05790.12790.0748-0.4482-0.19510.6536-0.3184-0.28740.2530.01920.0874-0.1128-0.1001-0.0389-0.0139-45.5621-4.74580.9865
22.20581.27951.04267.44973.15625.3748-0.04550.43-0.0434-0.524-0.0463-0.0768-0.21940.29130.09180.03420.06410.0044-0.1287-0.0086-0.1159-36.546-0.12733.9189
33.65040.73860.94159.51880.11842.64-0.08850.31550.0096-0.44240.2769-0.6229-0.34760.4278-0.18840.09480.06370.0704-0.1323-0.0789-0.1864-31.39284.84892.5586
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|1 - 68}A1 - 68
2X-RAY DIFFRACTION2{A|69 - 123}A69 - 123
3X-RAY DIFFRACTION3{A|124 - 183}A124 - 183

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