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- PDB-8pfl: Crystal structure of WRN helicase domain in complex with 3 -

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Basic information

Entry
Database: PDB / ID: 8pfl
TitleCrystal structure of WRN helicase domain in complex with 3
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 / 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
: / Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsScheufler, C. / Meyer, M. / Moebitz, H.
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.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _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)49,3583
Polymers48,6261
Non-polymers7322
Water6,305350
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area19250 Å2
Unit cell
Length a, b, c (Å)40.231, 87.484, 133.878
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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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: 48626.023 Da / Num. of mol.: 1 / Mutation: E625A, R564A, R785A, R803A, E886A, R942A
Source method: isolated from a genetically manipulated source
Details: WRN helicase domain with 6 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-YH8 / 2-[2-(3,6-dihydro-2~{H}-pyran-4-yl)-5-ethyl-7-oxidanylidene-6-[4-(3-oxidanylpyridin-2-yl)carbonylpiperazin-1-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-4-yl]-~{N}-[2-methyl-4-(trifluoromethyl)phenyl]ethanamide


Mass: 666.650 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H33F3N8O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 350 / 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: 2.42 Å3/Da / Density % sol: 49.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 30% Jeffamine ED-2001 0.1 M Hepes pH 7

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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 EIGER X 16M / Detector: PIXEL / Date: Aug 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.78→43.7 Å / Num. obs: 44341 / % possible obs: 95.8 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.066 / Rrim(I) all: 0.072 / Net I/σ(I): 15
Reflection shellResolution: 1.78→1.83 Å / Rmerge(I) obs: 1.096 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 2217 / CC1/2: 0.643 / Rrim(I) all: 1.191

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→35.26 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.944 / SU R Cruickshank DPI: 0.127 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.136 / SU Rfree Blow DPI: 0.123 / SU Rfree Cruickshank DPI: 0.119
RfactorNum. reflection% reflectionSelection details
Rfree0.2255 2215 -RANDOM
Rwork0.1968 ---
obs0.1983 43657 97.5 %-
Displacement parametersBiso mean: 35.67 Å2
Baniso -1Baniso -2Baniso -3
1-0.544 Å20 Å20 Å2
2--0.4811 Å20 Å2
3----1.0251 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: LAST / Resolution: 1.8→35.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3293 0 49 350 3692
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0093417HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.914629HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1207SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes588HARMONIC5
X-RAY DIFFRACTIONt_it3417HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion448SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3264SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.68
X-RAY DIFFRACTIONt_other_torsion13.96
LS refinement shellResolution: 1.8→1.82 Å
RfactorNum. reflection% reflection
Rfree0.2907 42 -
Rwork0.2604 --
obs0.2617 874 67.06 %
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)
11.25290.4084-1.68520.66090.02353.9908-0.2245-0.11440.343-0.11440.04020.21370.3430.21370.1843-0.01440.03520.012-0.00020.0144-0.0923-16.49-4.34726.3776
20.82680.3445-0.35660.9283-0.03090.61180.02480.00850.00570.0085-0.0069-0.00060.0057-0.0006-0.0179-0.0301-0.00630.0051-0.0136-0.016-0.0128-27.58273.176736.239
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|523 - A|724 }A523 - 724
2X-RAY DIFFRACTION2{ A|725 - A|944 }A725 - 944

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