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- PDB-9rus: Structure of WRN in complex with ATPgS and Compound 3 -

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Basic information

Entry
Database: PDB / ID: 9rus
TitleStructure of WRN in complex with ATPgS and Compound 3
ComponentsBifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
KeywordsHYDROLASE / DNA Damage Repair / Inhibitor / Complex / Helicase
Function / homology
Function and homology information


positive regulation of hydrolase activity / 3'-flap-structured DNA binding / positive regulation of strand invasion / forked DNA-dependent helicase activity / telomeric G-quadruplex DNA binding / 8-hydroxy-2'-deoxyguanosine DNA binding / telomeric D-loop binding / regulation of growth rate / telomere maintenance via semi-conservative replication / t-circle formation ...positive regulation of hydrolase activity / 3'-flap-structured DNA binding / positive regulation of strand invasion / forked DNA-dependent helicase activity / telomeric G-quadruplex DNA binding / 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 / four-way junction helicase activity / G-quadruplex DNA binding / bubble DNA binding / MutLalpha complex binding / Impaired BRCA2 binding to PALB2 / protein localization to nucleolus / Processive synthesis on the C-strand of the telomere / Removal of the Flap Intermediate from the C-strand / response to UV-C / exonuclease activity / 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 / HDR through Single Strand Annealing (SSA) / DNA 3'-5' helicase / DNA metabolic process / 3'-5' DNA helicase activity / DNA synthesis involved in DNA repair / Impaired BRCA2 binding to RAD51 / replication fork processing / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / mismatch repair / SUMOylation of DNA damage response and repair proteins / four-way junction DNA binding / 3'-5' exonuclease activity / telomere maintenance / DNA helicase activity / cellular response to starvation / replication fork / determination of adult lifespan / cellular response to gamma radiation / double-strand break repair via homologous recombination / G2/M DNA damage checkpoint / 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 / response to oxidative stress / Regulation of TP53 Activity through Phosphorylation / Hydrolases; Acting on ester bonds / chromosome, telomeric region / DNA replication / nuclear speck / DNA damage response / centrosome / 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'-DIPHOSPHATE / PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / 1-[(4-fluorophenyl)methyl]benzimidazole / Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.193 Å
AuthorsFletcher, C.T. / Rucktooa, P.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2025
Title: AI-assisted delivery of novel covalent WRN inhibitors from a non-covalent fragment screen.
Authors: Smith, G.M.T. / Aithani, L. / Barrett, C.E. / Bucher, A.O. / Cooper, C.D.O. / Degorce, S.L. / Dore, A.S. / Fletcher, C.T. / Huber, S. / Huckvale, R. / Kennedy, A.J. / Mornement, A.A. / ...Authors: Smith, G.M.T. / Aithani, L. / Barrett, C.E. / Bucher, A.O. / Cooper, C.D.O. / Degorce, S.L. / Dore, A.S. / Fletcher, C.T. / Huber, S. / Huckvale, R. / Kennedy, A.J. / Mornement, A.A. / Pickworth, M. / Rucktooa, P. / Scully, C.C.G. / Skerratt, S.E.
History
DepositionJul 4, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 22, 2025Provider: repository / Type: Initial release

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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
B: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,89716
Polymers97,1942
Non-polymers2,70314
Water3,243180
1
A: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,14410
Polymers48,5971
Non-polymers1,5479
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,7536
Polymers48,5971
Non-polymers1,1565
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.173, 91.173, 242.126
Angle α, β, γ (deg.)90, 90, 90
Int Tables number92
Space group name H-MP41212

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 48597.055 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
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 3'-5' helicase

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Non-polymers , 8 types, 194 molecules

#2: 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.: 2 / Source method: obtained synthetically / Formula: C10H16N5O12P3S / Comment: ATP-gamma-S, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-GQP / 1-[(4-fluorophenyl)methyl]benzimidazole


Mass: 226.249 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H11FN2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#8: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 18.015 Da / Num. of mol.: 180 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.59 Å3/Da / Density % sol: 52.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2 / Details: 0.1 mM MMT pH 7.2, 25 %w/v PEG 1500

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: May 4, 2023
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.193→85.324 Å / Num. obs: 37217 / % possible obs: 94.9 % / Redundancy: 26.68 % / Biso Wilson estimate: 52.5 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.1236 / Rpim(I) all: 0.0246 / Rrim(I) all: 0.1261 / Net I/σ(I): 17.92
Reflection shellResolution: 2.193→2.434 Å / Redundancy: 26.1 % / Rmerge(I) obs: 2.118 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1861 / CC1/2: 0.816 / Rpim(I) all: 0.419 / Rrim(I) all: 2.159 / % possible all: 74.6

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROC1.0.5 20230222data scaling
XDSJan 10, 2022data reduction
Aimless0.7.9data scaling
STARANISO2.3.92data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.193→85.32 Å / Cor.coef. Fo:Fc: 0.906 / Cor.coef. Fo:Fc free: 0.894 / SU R Cruickshank DPI: 0.659 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.715 / SU Rfree Blow DPI: 0.329 / SU Rfree Cruickshank DPI: 0.328
RfactorNum. reflection% reflectionSelection details
Rfree0.2978 1838 -RANDOM
Rwork0.267 ---
obs0.2686 37217 69.8 %-
Displacement parametersBiso mean: 63.02 Å2
Baniso -1Baniso -2Baniso -3
1-0.6047 Å20 Å20 Å2
2--0.6047 Å20 Å2
3----1.2094 Å2
Refine analyzeLuzzati coordinate error obs: 0.41 Å
Refinement stepCycle: LAST / Resolution: 2.193→85.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6377 0 160 180 6717
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0077426HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.910055HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2655SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1281HARMONIC5
X-RAY DIFFRACTIONt_it7426HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion970SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact5639SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.85
X-RAY DIFFRACTIONt_other_torsion19.17
LS refinement shellResolution: 2.193→2.32 Å
RfactorNum. reflection% reflection
Rfree0.3424 32 -
Rwork0.3037 --
obs--9.26 %

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