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- PDB-7ml8: The crystal structure of I38T mutant PA endonuclease (2009/H1N1/C... -

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Basic information

Entry
Database: PDB / ID: 7ml8
TitleThe crystal structure of I38T mutant PA endonuclease (2009/H1N1/CALIFORNIA) in complex with SJ001023038
ComponentsPolymerase acidic protein
KeywordsVIRAL PROTEIN/Inhibitor / NUCLEASE / INFLUENZA / INHIBITOR RESISTANCE / VIRAL PROTEIN / VIRAL PROTEIN-Inhibitor complex
Function / homology
Function and homology information


cap snatching / symbiont-mediated suppression of host mRNA transcription via inhibition of RNA polymerase II activity / endonuclease activity / host cell cytoplasm / Hydrolases; Acting on ester bonds / viral RNA genome replication / DNA-templated transcription / host cell nucleus / RNA binding / metal ion binding
Similarity search - Function
Polymerase acidic protein / Influenza RNA-dependent RNA polymerase subunit PA / Influenza RNA-dependent RNA polymerase subunit PA, endonuclease domain / Influenza RNA-dependent RNA polymerase subunit PA
Similarity search - Domain/homology
GLUTAMIC ACID / : / Hexa Vinylpyrrolidone K15 / Chem-ZHJ / Polymerase acidic protein
Similarity search - Component
Biological speciesInfluenza A virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsCuypers, M.G. / Slavish, P.J. / Yun, M.K. / Dubois, R. / Rankovic, Z. / White, S.W.
Citation
Journal: To Be Published
Title: The crystal structure of I38T mutant PA endonuclease (2009/H1N1/CALIFORNIA) in complex with St Jude compound AC067-19
Authors: Cuypers, M.G. / Slavish, P.J. / Yun, M.K. / Dubois, R. / Rankovic, Z. / White, S.W.
#1: Journal: Eur.J.Med.Chem. / Year: 2023
Title: Chemical scaffold recycling: Structure-guided conversion of an HIV integrase inhibitor into a potent influenza virus RNA-dependent RNA polymerase inhibitor designed to minimize resistance potential.
Authors: Slavish, P.J. / Cuypers, M.G. / Rimmer, M.A. / Abdolvahabi, A. / Jeevan, T. / Kumar, G. / Jarusiewicz, J.A. / Vaithiyalingam, S. / Jones, J.C. / Bowling, J.J. / Price, J.E. / DuBois, R.M. / ...Authors: Slavish, P.J. / Cuypers, M.G. / Rimmer, M.A. / Abdolvahabi, A. / Jeevan, T. / Kumar, G. / Jarusiewicz, J.A. / Vaithiyalingam, S. / Jones, J.C. / Bowling, J.J. / Price, J.E. / DuBois, R.M. / Min, J. / Webby, R.J. / Rankovic, Z. / White, S.W.
History
DepositionApr 27, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 27, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Revision 1.2Oct 18, 2023Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Polymerase acidic protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,6368
Polymers23,1361
Non-polymers1,4997
Water37821
1
A: Polymerase acidic protein
hetero molecules
x 8


Theoretical massNumber of molelcules
Total (without water)197,08564
Polymers185,0908
Non-polymers11,99556
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_665-x+1,-y+1,z1
crystal symmetry operation3_655-y+1,x,z1
crystal symmetry operation4_565y,-x+1,z1
crystal symmetry operation5_655-x+1,y,-z1
crystal symmetry operation6_565x,-y+1,-z1
crystal symmetry operation7_555y,x,-z1
crystal symmetry operation8_665-y+1,-x+1,-z1
Buried area18670 Å2
ΔGint-373 kcal/mol
Surface area60860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.644, 89.644, 133.729
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number97
Space group name H-MI422
Space group name HallI42
Symmetry operation#1: x,y,z
#2: -y,x,z
#3: y,-x,z
#4: x,-y,-z
#5: -x,y,-z
#6: -x,-y,z
#7: y,x,-z
#8: -y,-x,-z
#9: x+1/2,y+1/2,z+1/2
#10: -y+1/2,x+1/2,z+1/2
#11: y+1/2,-x+1/2,z+1/2
#12: x+1/2,-y+1/2,-z+1/2
#13: -x+1/2,y+1/2,-z+1/2
#14: -x+1/2,-y+1/2,z+1/2
#15: y+1/2,x+1/2,-z+1/2
#16: -y+1/2,-x+1/2,-z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Polymerase acidic protein / RNA-directed RNA polymerase subunit P2


Mass: 23136.289 Da / Num. of mol.: 1 / Mutation: I38T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus (strain swl A/California/04/2009 H1N1)
Strain: swl A/California/04/2009 H1N1 / Gene: PA / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: C3W5S0, Hydrolases; Acting on ester bonds

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Non-polymers , 6 types, 28 molecules

#2: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H9NO4
#3: Chemical ChemComp-ZHJ / 5-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-6-oxo-2-phenyl-1,6-dihydropyrimidine-4-carboxamide


Mass: 381.382 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19N3O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-QQ4 / Hexa Vinylpyrrolidone K15 / 1,1',1'',1''',1'''',1'''''-[(3R,5R,7R,9S,11R)-dodecane-1,3,5,7,9,11-hexayl]hexa(pyrrolidin-2-one)


Mass: 668.866 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H56N6O6
#5: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.9 Å3/Da / Density % sol: 57.63 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES PH 7.8, 1 M AMMONIUM SULFATE, 10 MM MNCL2, 10 MM MGCL2, 0.5% PVP K15

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Apr 14, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→74.46 Å / Num. obs: 7739 / % possible obs: 99.5 % / Redundancy: 5.9 % / Biso Wilson estimate: 65.3 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.056 / Rpim(I) all: 0.025 / Rrim(I) all: 0.062 / Χ2: 1.01 / Net I/σ(I): 20.4
Reflection shellResolution: 2.7→2.83 Å / Mean I/σ(I) obs: 1.9 / Num. unique obs: 997 / CC1/2: 0.678 / Rpim(I) all: 0.391 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5VPT

5vpt


Resolution: 2.7→74.46 Å / SU ML: 0.5982 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 32.8319
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2762 384 4.97 %
Rwork0.2313 7350 -
obs0.2335 7734 99.01 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 89.88 Å2
Refinement stepCycle: LAST / Resolution: 2.7→74.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1418 0 90 21 1529
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00151540
X-RAY DIFFRACTIONf_angle_d0.40472080
X-RAY DIFFRACTIONf_chiral_restr0.0365218
X-RAY DIFFRACTIONf_plane_restr0.0026261
X-RAY DIFFRACTIONf_dihedral_angle_d9.0507221
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-3.090.44851510.36772379X-RAY DIFFRACTION99.84
3.09-3.890.31731080.27512456X-RAY DIFFRACTION99.81
3.9-74.460.22351250.18712515X-RAY DIFFRACTION97.49
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)
12.35465132226-2.782342955660.6015858083317.284836851782.072874314256.75924057169-0.2596815133450.494540728013-0.5409026677530.0312225612714-0.1944406401830.2988812901670.4911718400720.1269754935830.3595701150270.913120554668-0.06401564351520.4231894501650.676981149342-0.06980290098790.77506593029934.411058459419.46423757833.85971955616
22.26889841323-0.8146733317361.970976400592.14703515775-0.6787949692724.63070592233-0.443004790043-0.531432328631-0.4270059650470.880928697916-0.246881869462-0.06648805410510.452379430250.663581481770.5947875848581.00040383281-0.007891744768020.3281702395790.8115676979110.3407436821290.76626565678145.390474018421.644878058720.1869906892
30.929649648127-1.537919927551.330699892043.00898840191-1.767854382852.323825287050.0484523971292-0.335581887493-0.358782678299-0.4125873021290.6197918271950.6840079603180.330113758286-0.74059908245-0.0964281334772.18246721812-0.4172569963980.53146625011.055444190880.377714412641.1215871307335.312354211610.457405177527.1004794563
42.90185022678-0.0251936310698-0.1769543125092.30939655816-0.812248181545.44395836834-0.345333427486-0.653633024767-0.7347266604280.649604140352-0.1568638651540.4559567231510.580303409928-0.418003294190.08708510259880.993267185732-0.1356269586260.515398392340.8252162200690.08158354025610.83038306835829.908129820522.338776106422.4232879099
52.14553881356-1.49627074131-2.287205063277.021276275224.375243646483.731101604240.360330038863-0.138889054876-1.457313749030.808030447492-0.339318266603-0.7745873153981.64865108473-0.01312030455730.2609857723431.71559158689-0.08739966514160.6330073166020.6931968708970.2377292933722.0401300280229.32106777839.9226827374717.9913856402
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A

IDRefine TLS-IDSelection detailsLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid -3 through 31 )A-3 - 311 - 35
22chain 'A' and (resid 32 through 126 )A32 - 12636 - 111
33chain 'A' and (resid 127 through 138 )A127 - 138112 - 123
44chain 'A' and (resid 139 through 194 )A139 - 194124 - 179
55chain 'A' and (resid 202 through 202 )B2021

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