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

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Basic information

Entry
Database: PDB / ID: 7rkp
TitleThe crystal structure of I38T mutant PA endonuclease (2009/H1N1/CALIFORNIA) in complex with cyclic compound SJ001034733
ComponentsPolymerase acidic protein
KeywordsViral Protein / Hydrolase / NUCLEASE / INFLUENZA / INHIBITOR RESISTANCE / 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
Chem-5Y1 / : / Hexa Vinylpyrrolidone K15 / Polymerase acidic protein
Similarity search - Component
Biological speciesInfluenza A virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.36 Å
AuthorsCuypers, M.G. / Slavish, J.P. / Rankovic, Z. / White, S.W.
Citation
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.
#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
DepositionJul 22, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 29, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 11, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Revision 1.3Oct 25, 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)24,6258
Polymers23,1361
Non-polymers1,4887
Water905
1
A: Polymerase acidic protein
hetero molecules

A: Polymerase acidic protein
hetero molecules

A: Polymerase acidic protein
hetero molecules

A: Polymerase acidic protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,49932
Polymers92,5454
Non-polymers5,95428
Water724
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
Buried area7730 Å2
ΔGint-226 kcal/mol
Surface area33410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.690, 89.690, 133.156
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 / Cell line: 2009 / Gene: PA / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: C3W5S0, Hydrolases; Acting on ester bonds

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Non-polymers , 5 types, 12 molecules

#2: 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
#3: Chemical ChemComp-5Y1 / (5R)-5-hydroxy-16,21-dioxa-3,8,28-triazatetracyclo[20.3.1.1~2,6~.1~11,15~]octacosa-1(26),2,6(28),11(27),12,14,22,24-octaene-4,7-dione


Mass: 421.446 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23N3O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MN / MANGANESE (II) ION


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


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 2.89 Å3/Da / Density % sol: 57.49 %
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: Jul 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.36→74.39 Å / Num. obs: 11501 / % possible obs: 99.9 % / Redundancy: 5.4 % / Biso Wilson estimate: 55 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.042 / Rpim(I) all: 0.02 / Χ2: 0.65 / Net I/σ(I): 21.1
Reflection shellResolution: 2.36→2.45 Å / Redundancy: 5.2 % / Mean I/σ(I) obs: 1.9 / Num. unique obs: 1162 / CC1/2: 0.853 / Rpim(I) all: 0.378 / Χ2: 0.65 / % possible all: 99.1

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5vpt

5vpt


Resolution: 2.36→45.92 Å / SU ML: 0.3304 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.3684
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2551 590 5.13 %
Rwork0.2262 10902 -
obs0.2277 11492 99.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 72.68 Å2
Refinement stepCycle: LAST / Resolution: 2.36→45.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1456 0 89 5 1550
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0021578
X-RAY DIFFRACTIONf_angle_d0.56482133
X-RAY DIFFRACTIONf_chiral_restr0.0392220
X-RAY DIFFRACTIONf_plane_restr0.0027270
X-RAY DIFFRACTIONf_dihedral_angle_d8.4726231
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.36-2.60.31861570.29852625X-RAY DIFFRACTION99.36
2.6-2.970.32761390.2932706X-RAY DIFFRACTION99.86
2.97-3.750.29971420.23842723X-RAY DIFFRACTION100
3.75-45.920.21261520.19822848X-RAY DIFFRACTION99.37
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)
12.36121072545-1.529400977110.3459265383066.87543046011-2.20155626243.27196706441-0.329223024098-0.164151315112-0.1126684530240.7829473922610.16287222298-0.275186155333-0.276268637051-0.1706617137630.04991760844980.520951055864-0.0749761008314-0.0206937123170.640195381819-0.2591963770220.4671861919521.99651997534.1726434668-4.03492785974
22.74156107481-4.105810524962.541345970059.70336503694-3.123223631763.04419262114-0.170357312213-0.2253769634570.2870583661790.5830708220850.3547052846261.14448958663-0.66926258851-0.802384086067-0.1931950117460.5550875765940.02328599347040.1197261097691.16559742509-0.2059376746160.922589566611.840691204436.3263727797-3.3328309395
30.246353953403-0.388449635192-0.07030208091773.91438224681-0.439522436220.853411987107-0.1325275798580.02269718274180.1659163325360.15113451864-0.00886432270841-0.0669051339209-0.398456784722-0.1052446617770.1374272980130.458064799938-0.109545239847-0.1132618312990.620538774398-0.2386356212650.54837968145925.133273987841.0275220958-16.5169152164
41.868290956070.7986099990970.9613411898445.022520214730.9152727894121.98119227501-0.2664867300690.4467085616210.352883703009-0.715413238585-0.1154158412420.771669925958-0.359335510504-0.8945408514780.1431712526240.580482884843-0.00995701455385-0.2521397524120.816450371326-0.1863482068990.59399010085518.813630011148.5686870954-22.8136046296
52.861407810010.4333263507231.650420449443.307617918221.11044412212.22094240203-0.006610313460360.0805128778734-0.301770831225-0.672236930938-0.01787743677350.8167924225780.068407423602-0.132981542762-0.2391949414970.78588458916-0.246685442003-0.2762185525581.92787631179-0.1655059693260.85226649498210.852241688534.8534446218-27.3957937204
60.725597038540.235447835784-0.1472287145834.68175012107-1.582922522833.78009771089-0.07082394138290.336752954662-0.230211124687-0.4288430922460.04350040641560.6273474457320.623116220799-0.6768591286570.01610574923470.550304478949-0.17394147131-0.03430472125680.762722476161-0.291339680030.56807729950822.029195923730.1629792644-22.3236998616
Refinement TLS group

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

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid -3 through 23 )-3 - 231 - 27
22chain 'A' and (resid 24 through 31 )24 - 3128 - 35
33chain 'A' and (resid 32 through 83 )32 - 8336 - 68
44chain 'A' and (resid 84 through 126 )84 - 12669 - 111
55chain 'A' and (resid 127 through 137 )127 - 137112 - 122
66chain 'A' and (resid 138 through 195 )138 - 195123 - 180

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