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- PDB-7gqt: Crystal Structure of Werner helicase fragment 517-945 in complex ... -

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Basic information

Entry
Database: PDB / ID: 7gqt
TitleCrystal Structure of Werner helicase fragment 517-945 in complex with ATP
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 / 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 / telomeric D-loop disassembly ...3'-flap-structured DNA binding / positive regulation of strand invasion / telomeric G-quadruplex DNA binding / 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 / telomeric D-loop disassembly / DNA geometric change / Y-form DNA binding / G-quadruplex DNA binding / bubble DNA binding / MutLalpha complex binding / Impaired BRCA2 binding to PALB2 / Processive synthesis on the C-strand of the telomere / protein localization to nucleolus / Removal of the Flap Intermediate from the C-strand / response to UV-C / Homologous DNA Pairing and Strand Exchange / 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 / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / exonuclease activity / 3'-5' DNA helicase activity / Resolution of D-loop Structures through Holliday Junction Intermediates / DNA 3'-5' helicase / HDR through Single Strand Annealing (SSA) / DNA metabolic process / Impaired BRCA2 binding to RAD51 / DNA synthesis involved in DNA repair / replication fork processing / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / SUMOylation of DNA damage response and repair proteins / DNA helicase activity / four-way junction DNA binding / 3'-5' exonuclease activity / telomere maintenance / cellular response to starvation / replication fork / determination of adult lifespan / isomerase activity / double-strand break repair via homologous recombination / G2/M DNA damage checkpoint / cellular response to gamma radiation / base-excision repair / HDR through Homologous Recombination (HRR) / cellular senescence / double-strand break repair / manganese ion binding / chromosome / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / response to oxidative stress / Hydrolases; Acting on ester bonds / forked DNA-dependent helicase activity / single-stranded 3'-5' DNA helicase activity / four-way junction helicase activity / double-stranded DNA helicase activity / chromosome, telomeric region / DNA replication / 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 / Helicase and RNase D C-terminal / HRDC domain / HRDC domain / HRDC domain profile. / ATP-dependent DNA helicase RecQ, zinc-binding domain ...Helicase Helix-turn-helix domain / Helix-turn-helix domain / RQC domain / RQC / RQC domain / Helicase and RNase D C-terminal / HRDC domain / HRDC domain / HRDC domain profile. / ATP-dependent DNA helicase RecQ, zinc-binding domain / RecQ zinc-binding / DNA helicase, ATP-dependent, RecQ type / HRDC domain superfamily / 3'-5' exonuclease / 3'-5' exonuclease / 3'-5' exonuclease domain / HRDC-like superfamily / DEAD/DEAH box helicase domain / DEAD/DEAH box helicase / 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'-TRIPHOSPHATE / Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.21 Å
AuthorsClassen, M. / Benz, J. / Brugger, D. / 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)50,7275
Polymers50,0651
Non-polymers6624
Water1,22568
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)50.227, 90.227, 54.002
Angle α, β, γ (deg.)90.000, 102.820, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#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
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / Source method: isolated from a natural source / Formula: H2O
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: 2.38 Å3/Da / Density % sol: 48.39 %
Crystal growTemperature: 277 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 20nL with 20nL seed solution and 110nL reservoir consisting of 0.2M NaCl, 0.1M Na/K Phosphate, 10%w/v PEG8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99997 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 13, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 2.21→52.66 Å / Num. obs: 23329 / % possible obs: 98.7 % / Redundancy: 6.866 % / Biso Wilson estimate: 28.12 Å2 / CC1/2: 0.988 / Rmerge(I) obs: 0.433 / Rrim(I) all: 0.469 / Χ2: 0.688 / Net I/σ(I): 4.99 / Num. measured all: 160168 / Scaling rejects: 114
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
2.21-2.275.4235.5260.258292174715290.156.12287.5
2.27-2.336.2923.4610.4810608170016860.153.7899.2
2.33-2.47.1243.1930.6111790166016550.3413.44499.7
2.4-2.477.242.4730.8711483159015860.4342.66499.7
2.47-2.557.212.1041.0811045154015320.5142.26899.5
2.55-2.647.141.8571.2410910153315280.5332.00499.7
2.64-2.747.0571.6571.519901140614030.6511.78999.8
2.74-2.856.8371.25729593140814030.7311.36199.6
2.85-2.986.5821.0472.438767134213320.7841.13899.3
2.98-3.137.1050.8543.299123128512840.8590.92199.9
3.13-3.297.2430.5958720121112040.9390.63699.4
3.29-3.497.1190.4766.678166114911470.9710.51399.8
3.49-3.747.0080.3938.437555108710780.9790.42599.2
3.74-4.036.7740.35110.256876101710150.9770.3899.8
4.03-4.426.5040.28512.960239259260.980.311100
4.42-4.947.2380.25615.4162398618620.9910.276100
4.94-5.717.3270.25114.9654667507460.9890.2799.5
5.71-6.997.1080.25413.3944926326320.9920.274100
6.99-9.886.460.10820.3132044984960.9950.11899.6
9.88-52.666.7190.0583119152882850.9960.06399

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIXdev_4357refinement
PDB_EXTRACT3.28data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.21→52.66 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.42 / Phase error: 29.17 / Stereochemistry target values: ML
Details: gamma-phosphate has higher B-values than beta-phosphate, indicating that it might be a mixture of ADPATP.
RfactorNum. reflection% reflectionSelection details
Rfree0.263 711 5.16 %RANDOM
Rwork0.2048 13058 --
obs0.2078 13769 58.6 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 140.84 Å2 / Biso mean: 41.5418 Å2 / Biso min: 16.46 Å2
Refinement stepCycle: final / Resolution: 2.21→52.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3346 0 34 68 3448
Biso mean--37.6 30.54 -
Num. residues----421
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.21-2.380.332240.286452755112
2.38-2.620.3469960.27321571166736
2.62-30.35641570.27152685284260
3-3.780.26382050.21053900410588
3.78-52.660.22372290.17244375460497
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)
14.30591.1516-1.05113.47090.12675.0196-0.15550.0905-0.2885-0.27890.1597-0.10930.14280.0706-0.02990.2647-0.0619-0.02110.1328-0.0040.18014.5209-12.484-25.9552
24.16120.7838-0.48934.50030.24532.86340.0312-0.01090.1335-0.10040.06760.5180.2099-0.5729-0.10950.3137-0.0321-0.0410.33230.05440.2196-11.4105-1.4013-24.8807
31.10390.39920.38412.8330.91771.89120.0719-0.08240.1596-0.1323-0.07410.031-0.0869-0.0282-0.00030.10620.02560.00920.20010.0360.13195.66477.0421-7.0736
40.8945-0.0890.42723.0862-0.563.14070.0264-0.1564-0.15150.07060.06690.0250.3428-0.1877-0.01770.1196-0.01060.02450.2074-0.00870.23878.15743.7373-1.8247
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 527 through 576 )A527 - 576
2X-RAY DIFFRACTION2chain 'A' and (resid 577 through 693 )A577 - 693
3X-RAY DIFFRACTION3chain 'A' and (resid 694 through 799 )A694 - 799
4X-RAY DIFFRACTION4chain 'A' and (resid 800 through 952 )A800 - 952

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