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- PDB-8pfp: Crystal structure of WRN helicase domain in complex with ATPgammaS -

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Basic information

Entry
Database: PDB / ID: 8pfp
TitleCrystal structure of WRN helicase domain in complex with ATPgammaS
ComponentsBifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
KeywordsHYDROLASE / Inhibitor / Complex
Function / homology
Function and homology information


3'-flap-structured DNA binding / positive regulation of strand invasion / forked DNA-dependent helicase activity / 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 / G-quadruplex DNA unwinding ...3'-flap-structured DNA binding / positive regulation of strand invasion / forked DNA-dependent helicase activity / 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 / G-quadruplex DNA unwinding / t-circle formation / 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 / response to UV-C / DNA 3'-5' helicase / 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) / Resolution of D-loop Structures through Holliday Junction Intermediates / exonuclease activity / DNA metabolic process / DNA duplex unwinding / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / 3'-5' DNA helicase activity / DNA synthesis involved in DNA repair / DNA unwinding involved in DNA replication / replication fork processing / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / SUMOylation of DNA damage response and repair proteins / four-way junction DNA binding / 3'-5' exonuclease activity / DNA helicase activity / telomere maintenance / cellular response to starvation / determination of adult lifespan / replication fork / isomerase activity / double-strand break repair via homologous recombination / base-excision repair / G2/M DNA damage checkpoint / HDR through Homologous Recombination (HRR) / cellular response to gamma radiation / 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 / DNA replication / 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 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
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsScheufler, C. / Villard, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2024
Title: Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.
Authors: Ferretti, S. / Hamon, J. / de Kanter, R. / Scheufler, C. / Andraos-Rey, R. / Barbe, S. / Bechter, E. / Blank, J. / Bordas, V. / Dammassa, E. / Decker, A. / Di Nanni, N. / Dourdoigne, M. / ...Authors: Ferretti, S. / Hamon, J. / de Kanter, R. / Scheufler, C. / Andraos-Rey, R. / Barbe, S. / Bechter, E. / Blank, J. / Bordas, V. / Dammassa, E. / Decker, A. / Di Nanni, N. / Dourdoigne, M. / Gavioli, E. / Hattenberger, M. / Heuser, A. / Hemmerlin, C. / Hinrichs, J. / Kerr, G. / Laborde, L. / Jaco, I. / Nunez, E.J. / Martus, H.J. / Quadt, C. / Reschke, M. / Romanet, V. / Schaeffer, F. / Schoepfer, J. / Schrapp, M. / Strang, R. / Voshol, H. / Wartmann, M. / Welly, S. / Zecri, F. / Hofmann, F. / Mobitz, H. / Cortes-Cros, M.
History
DepositionJun 16, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 22, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)49,3293
Polymers48,7401
Non-polymers5892
Water3,693205
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area820 Å2
ΔGint-3 kcal/mol
Surface area18470 Å2
Unit cell
Length a, b, c (Å)46.964, 47.707, 55.021
Angle α, β, γ (deg.)82.37, 67.15, 63.65
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN / DNA helicase / RecQ-like type 3 / RecQ protein-like 2 / Werner syndrome protein


Mass: 48740.156 Da / Num. of mol.: 1 / Mutation: E625A, R716A, K804A, E886A, R942A
Source method: isolated from a genetically manipulated source
Details: WRN helicase domain with 5 surface mutations. / Source: (gene. exp.) Homo sapiens (human) / Gene: WRN, RECQ3, RECQL2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q14191, Hydrolases; Acting on ester bonds, DNA helicase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-AGS / PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-GAMMA-S / ADENOSINE 5'-(3-THIOTRIPHOSPHATE) / ADENOSINE 5'-(GAMMA-THIOTRIPHOSPHATE) / ADENOSINE-5'-DIPHOSPHATE MONOTHIOPHOSPHATE


Mass: 523.247 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O12P3S / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP-gamma-S, energy-carrying molecule analogue*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / 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: 2.09 Å3/Da / Density % sol: 41.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 20 % PEG3350 0.2 M Sodium citrate tribasic dihydrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.58→40 Å / Num. obs: 50497 / % possible obs: 93.4 % / Redundancy: 1.8 % / CC1/2: 0.999 / Net I/σ(I): 12.8
Reflection shellResolution: 1.58→1.62 Å / Mean I/σ(I) obs: 1.14 / Num. unique obs: 3742 / CC1/2: 0.561

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→26.64 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.952 / SU R Cruickshank DPI: 0.107 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.107 / SU Rfree Blow DPI: 0.102 / SU Rfree Cruickshank DPI: 0.103
RfactorNum. reflection% reflectionSelection details
Rfree0.2384 2433 -RANDOM
Rwork0.2118 ---
obs0.2131 48675 93.5 %-
Displacement parametersBiso mean: 32.55 Å2
Baniso -1Baniso -2Baniso -3
1-1.4345 Å2-1.9359 Å2-1.8286 Å2
2---0.5288 Å2-0.5468 Å2
3----0.9057 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: LAST / Resolution: 1.6→26.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3155 0 32 205 3392
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013252HARMONIC2
X-RAY DIFFRACTIONt_angle_deg14407HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1123SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes541HARMONIC5
X-RAY DIFFRACTIONt_it3252HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion436SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3022SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.56
X-RAY DIFFRACTIONt_other_torsion15.47
LS refinement shellResolution: 1.6→1.61 Å
RfactorNum. reflection% reflection
Rfree0.3757 48 -
Rwork0.3002 --
obs0.3037 974 93.96 %
Refinement TLS params.Method: refined / Origin x: -16.1238 Å / Origin y: 3.4805 Å / Origin z: 11.2275 Å
111213212223313233
T-0.0691 Å20.0003 Å2-0.0107 Å2--0.018 Å20.0054 Å2---0.0129 Å2
L0.3451 °2-0.1653 °2-0.3451 °2-0.5208 °20.3178 °2--0.9693 °2
S0.0025 Å °0.0155 Å °-0.0015 Å °0.0155 Å °-0.0268 Å °-0.0135 Å °-0.0015 Å °-0.0135 Å °0.0243 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|525 - A|944 A|2001 - A|2001 A|2002 - A|2002 }A525 - 944
2X-RAY DIFFRACTION1{ A|525 - A|944 A|2001 - A|2001 A|2002 - A|2002 }A2001
3X-RAY DIFFRACTION1{ A|525 - A|944 A|2001 - A|2001 A|2002 - A|2002 }A2002

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