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- PDB-7gqu: Crystal Structure of Werner helicase fragment 517-945 in covalent... -

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Basic information

Entry
Database: PDB / ID: 7gqu
TitleCrystal Structure of Werner helicase fragment 517-945 in covalent complex with N-[(E,1S)-1-cyclopropyl-3-methylsulfonylprop-2-enyl]-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide
ComponentsBifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
KeywordsHYDROLASE / HELICASE / WERNER SYNDROME / DNA REPAIR
Function / homology
Function and homology information


3'-flap-structured DNA binding / positive regulation of strand invasion / telomeric G-quadruplex DNA binding / forked DNA-dependent helicase activity / positive regulation of hydrolase activity / 8-hydroxy-2'-deoxyguanosine DNA binding / telomeric D-loop binding / regulation of growth rate / telomere maintenance via semi-conservative replication / t-circle formation ...3'-flap-structured DNA binding / positive regulation of strand invasion / telomeric G-quadruplex DNA binding / forked DNA-dependent helicase activity / positive regulation of hydrolase activity / 8-hydroxy-2'-deoxyguanosine DNA binding / telomeric D-loop binding / regulation of growth rate / telomere maintenance via semi-conservative replication / t-circle formation / G-quadruplex DNA unwinding / telomeric D-loop disassembly / Y-form DNA binding / four-way junction helicase activity / G-quadruplex DNA binding / MutLalpha complex binding / bubble DNA binding / Processive synthesis on the C-strand of the telomere / Impaired BRCA2 binding to PALB2 / Removal of the Flap Intermediate from the C-strand / protein localization to nucleolus / DNA 3'-5' helicase / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Homologous DNA Pairing and Strand Exchange / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / exonuclease activity / response to UV-C / Resolution of D-loop Structures through Holliday Junction Intermediates / DNA duplex unwinding / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / DNA metabolic process / DNA synthesis involved in DNA repair / replication fork processing / DNA unwinding involved in DNA replication / 3'-5' DNA helicase activity / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / SUMOylation of DNA damage response and repair proteins / four-way junction DNA binding / DNA helicase activity / isomerase activity / 3'-5' exonuclease activity / cellular response to starvation / telomere maintenance / replication fork / determination of adult lifespan / double-strand break repair via homologous recombination / base-excision repair / HDR through Homologous Recombination (HRR) / G2/M DNA damage checkpoint / cellular response to gamma radiation / cellular senescence / double-strand break repair / chromosome / manganese ion binding / Processing of DNA double-strand break ends / DNA replication / Regulation of TP53 Activity through Phosphorylation / response to oxidative stress / chromosome, telomeric region / Hydrolases; Acting on ester bonds / nuclear speck / centrosome / DNA damage response / chromatin binding / protein-containing complex binding / nucleolus / magnesium ion binding / protein homodimerization activity / ATP hydrolysis activity / DNA binding / nucleoplasm / ATP binding / nucleus / cytoplasm
Similarity search - Function
Helicase Helix-turn-helix domain / Helix-turn-helix domain / RQC domain / RQC / RQC domain / ATP-dependent DNA helicase RecQ, zinc-binding domain / RecQ zinc-binding / DNA helicase, ATP-dependent, RecQ type / Helicase and RNase D C-terminal / HRDC domain ...Helicase Helix-turn-helix domain / Helix-turn-helix domain / RQC domain / RQC / RQC domain / ATP-dependent DNA helicase RecQ, zinc-binding domain / RecQ zinc-binding / DNA helicase, ATP-dependent, RecQ type / Helicase and RNase D C-terminal / HRDC domain / HRDC domain / HRDC domain profile. / HRDC domain superfamily / 3'-5' exonuclease / 3'-5' exonuclease / 3'-5' exonuclease domain / HRDC-like superfamily / DEAD/DEAH box helicase / DEAD/DEAH box helicase domain / Helicase conserved C-terminal domain / helicase superfamily c-terminal domain / 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 / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / : / Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.54 Å
AuthorsClassen, M. / Benz, J. / Brugger, D. / Tagliente, O. / Rudolph, M.G.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
F. Hoffmann-La Roche LTD Switzerland
CitationJournal: Nature / Year: 2024
Title: Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.
Authors: Baltgalvis, K.A. / Lamb, K.N. / Symons, K.T. / Wu, C.C. / Hoffman, M.A. / Snead, A.N. / Song, X. / Glaza, T. / Kikuchi, S. / Green, J.C. / Rogness, D.C. / Lam, B. / Rodriguez-Aguirre, M.E. / ...Authors: Baltgalvis, K.A. / Lamb, K.N. / Symons, K.T. / Wu, C.C. / Hoffman, M.A. / Snead, A.N. / Song, X. / Glaza, T. / Kikuchi, S. / Green, J.C. / Rogness, D.C. / Lam, B. / Rodriguez-Aguirre, M.E. / Woody, D.R. / Eissler, C.L. / Rodiles, S. / Negron, S.M. / Bernard, S.M. / Tran, E. / Pollock, J. / Tabatabaei, A. / Contreras, V. / Williams, H.N. / Pastuszka, M.K. / Sigler, J.J. / Pettazzoni, P. / Rudolph, M.G. / Classen, M. / Brugger, D. / Claiborne, C. / Plancher, J.M. / Cuartas, I. / Seoane, J. / Burgess, L.E. / Abraham, R.T. / Weinstein, D.S. / Simon, G.M. / Patricelli, M.P. / Kinsella, T.M.
History
DepositionOct 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2May 29, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,1126
Polymers50,0651
Non-polymers1,0475
Water3,657203
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, elutes as a monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.255, 83.802, 119.624
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN


Mass: 50064.746 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WRN / Plasmid: pFastBac1_hWRN(517-945)_C-H3CV-GFP-10His / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q14191

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Non-polymers , 6 types, 208 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#4: Chemical ChemComp-X1L / N-[(1S)-1-cyclopropyl-3-(methanesulfonyl)propyl]-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide


Mass: 439.476 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23F2N3O4S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 203 / 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: 2.32 Å3/Da / Density % sol: 46.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.2
Details: 5 mg/mL protein in 20mM TRIS/HCl pH7.5, 350mM NaCl, 0.25mM TCEP, 2.5% glycerol mixed 40nL with 180nL reservoir consisting of 20 %v/v Ethylene glycol, 11 %w/v PEG8000, 0.08M MES/NaOH pH6.2, 0.08M imidazole

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Dec 16, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.54→68.64 Å / Num. obs: 69059 / % possible obs: 99.2 % / Redundancy: 6.752 % / Biso Wilson estimate: 25.84 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.045 / Rrim(I) all: 0.049 / Χ2: 0.865 / Net I/σ(I): 14.65 / Num. measured all: 466266 / Scaling rejects: 92
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.54-1.587.0482.5060.6234696507149230.3062.70397.1
1.58-1.626.9961.9850.8334126494648780.3872.14298.6
1.62-1.676.981.4061.2433056480847360.5511.51898.5
1.67-1.726.8591.0031.7731859470446450.731.08498.7
1.72-1.786.7340.7322.4230487456945270.8110.79399.1
1.78-1.846.3610.4933.4327828438743750.8930.53799.7
1.84-1.916.6310.3634.8128057425942310.9350.39499.3
1.91-1.997.0990.2716.7428856409240650.9750.29299.3
1.99-2.087.0640.1839.8927732394539260.9880.19899.5
2.08-2.186.9370.13313.1126000376437480.9930.14499.6
2.18-2.36.8220.09617.0624382358635740.9960.10499.7
2.3-2.436.6210.07920.9322683343634260.9960.08599.7
2.43-2.66.1890.06224.3619717319431860.9970.06899.7
2.6-2.816.5860.05130.8919671299629870.9980.05599.7
2.81-3.086.8750.04137.1919120278527810.9990.04499.9
3.08-3.446.750.03543.1116908251125050.9990.03899.8
3.44-3.986.5590.0347.2814738224922470.9990.03299.9
3.98-4.875.9920.02847.9511379190618990.9990.03199.6
4.87-6.896.3060.02948.219554152715150.9990.03199.2
6.89-43.146.1210.02650.3954178948850.9990.02899

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.28data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 1.54→43.14 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.39 / Stereochemistry target values: ML
Details: Covalent adduct, used two alternative ligand conformations to expain alternate Cys conformations
RfactorNum. reflection% reflectionSelection details
Rfree0.2088 2836 4.92 %RANDOM
Rwork0.1795 54847 --
obs0.1809 57683 82.2 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 138.24 Å2 / Biso mean: 39.3109 Å2 / Biso min: 16.81 Å2
Refinement stepCycle: final / Resolution: 1.54→43.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3342 0 95 204 3641
Biso mean--29.73 39.74 -
Num. residues----419
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.54-1.560.230630.303891943
1.56-1.590.3232250.257141343813
1.59-1.620.316500.2862989103930
1.62-1.650.28521060.26441755186154
1.65-1.690.30091370.24942325246271
1.69-1.730.28511300.23362664279480
1.73-1.770.28431470.23023091323893
1.77-1.820.25221640.21993266343099
1.82-1.870.23371630.21653269343299
1.87-1.940.25921620.21553313347599
1.94-20.25131780.215733043482100
2-2.080.20821660.200632973463100
2.08-2.180.24871500.186833293479100
2.18-2.290.24281770.190233173494100
2.29-2.440.22541710.189733523523100
2.44-2.630.21781760.189133243500100
2.63-2.890.22581810.19233823563100
2.89-3.310.20891900.180133623552100
3.31-4.170.18091820.155934173599100
4.17-43.140.16781780.149935873765100
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)
12.5214-0.5998-0.72453.17351.42292.90980.18940.28880.2352-0.4151-0.13860.0539-0.4813-0.4359-0.02910.2330.07620.03920.20650.04270.156810.657937.85656.933
22.41351.0171-1.58651.6423-0.89812.85740.067-0.2609-0.18190.0854-0.1028-0.00630.1232-0.04190.00930.18120.01040.00460.10220.00310.146-0.616818.519524.5151
33.90920.0303-0.59481.2873-0.28842.02310.03260.208-0.2492-0.186-0.1198-0.010.1285-0.01950.08210.2014-0.02050.01040.188-0.00020.17790.15819.505120.2463
43.36580.2057-0.21645.61241.74965.83080.015-0.659-0.39320.2716-0.0882-0.46280.21020.46770.04840.15520.007-0.06820.3580.14490.358316.884415.828826.647
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and ((resid 527 through 718 ) or (resid 1001))A0
2X-RAY DIFFRACTION2chain 'A' and ((resid 719 through 799 ) or (resid 1002))A0
3X-RAY DIFFRACTION3chain 'A' and (resid 800 through 885 )A800 - 885
4X-RAY DIFFRACTION4chain 'A' and ((resid 886 through 945 ) or (resid 1000))A0

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