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- PDB-9mk1: Crystal structure of WRN helicase with bound compound 6 -

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Basic information

Entry
Database: PDB / ID: 9mk1
TitleCrystal structure of WRN helicase with bound compound 6
ComponentsBifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
KeywordsHYDROLASE / WRN / Werner / 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 / DNA geometric change ...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 / DNA geometric change / Y-form DNA binding / telomeric D-loop disassembly / t-circle formation / 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 / response to UV-C / Removal of the Flap Intermediate from the C-strand / 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 metabolic process / DNA synthesis involved in DNA repair / 3'-5' DNA helicase activity / Impaired BRCA2 binding to RAD51 / DNA 3'-5' helicase / 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 / DNA helicase activity / telomere maintenance / 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 / DNA replication / chromosome, telomeric region / 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 / ATP-dependent DNA helicase RecQ, zinc-binding domain / RecQ zinc-binding / HRDC domain / HRDC domain ...Helicase Helix-turn-helix domain / Helix-turn-helix domain / RQC domain / RQC / RQC domain / Helicase and RNase D C-terminal / ATP-dependent DNA helicase RecQ, zinc-binding domain / RecQ zinc-binding / HRDC domain / HRDC domain / DNA helicase, ATP-dependent, RecQ type / 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
: / Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.12 Å
AuthorsPalte, R.L. / Koglin, M. / Maskos, K. / Tauchert, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2026
Title: WRN structural flexibility showcased through fragment-based lead discovery of inhibitors.
Authors: Palte, R.L. / Mandal, M. / Sikorska, J. / Villafania, A.B. / Rickard, M.M. / Bauer, R.J. / Buevich, A.V. / Chai, X. / He, J. / Hussain, Z. / Koglin, M. / MacDonald, H.B. / Mansueto, M.S. / ...Authors: Palte, R.L. / Mandal, M. / Sikorska, J. / Villafania, A.B. / Rickard, M.M. / Bauer, R.J. / Buevich, A.V. / Chai, X. / He, J. / Hussain, Z. / Koglin, M. / MacDonald, H.B. / Mansueto, M.S. / Maskos, K. / Methot, J.L. / Robustelli, J. / Soriano, A. / Tauchert, M.J. / Tyagarajan, S. / Zhang, M. / Klein, D.J. / Hicks, J.D. / McLaren, D.G. / Gabelli, S.B. / Wyss, D.F.
History
DepositionDec 16, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2026Group: 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)51,2365
Polymers50,4811
Non-polymers7554
Water1,42379
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area390 Å2
ΔGint7 kcal/mol
Surface area19800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.820, 57.750, 133.530
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 50480.906 Da / Num. of mol.: 1 / Fragment: UNP residues 500-942
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
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-A1BL8 / (2-[(2R)-2-(phenylcarbamoyl)-2,3-dihydro-1H-inden-4-yl]-5-{[4-(trifluoromethyl)phenyl]carbamoyl}-1,3-thiazol-4-yl)acetic acid


Mass: 565.563 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H22F3N3O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / Source method: isolated from a natural source / Formula: H2O
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: 2.21 Å3/Da / Density % sol: 44.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 24.5% w/v PEG1500, 0.1 M MMT, pH 6.0

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.8856 Å
DetectorType: DECTRIS EIGER2 X CdTe 16M / Detector: PIXEL / Date: Nov 6, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8856 Å / Relative weight: 1
ReflectionResolution: 2.12→53.06 Å / Num. obs: 26085 / % possible obs: 99.4 % / Redundancy: 7.3 % / CC1/2: 0.997 / Rsym value: 0.094 / Net I/σ(I): 12.1
Reflection shellResolution: 2.12→2.15 Å / Redundancy: 6.6 % / Num. unique obs: 1251 / CC1/2: 0.564

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION Jun 30data reduction
autoPROC(Version 1.1.7)data scaling
XSCALE(data scaling
REFMAC5.8.0267refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.12→53.06 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.918 / SU B: 7.489 / SU ML: 0.188 / Cross valid method: THROUGHOUT / ESU R: 0.278 / ESU R Free: 0.215 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26659 1252 4.8 %RANDOM
Rwork0.22801 ---
obs0.22987 24831 99.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 47.055 Å2
Baniso -1Baniso -2Baniso -3
1--1.21 Å20 Å2-0 Å2
2--0.93 Å2-0 Å2
3---0.28 Å2
Refinement stepCycle: LAST / Resolution: 2.12→53.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3368 0 49 79 3496
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0133485
X-RAY DIFFRACTIONr_bond_other_d0.0020.0173299
X-RAY DIFFRACTIONr_angle_refined_deg1.3481.664721
X-RAY DIFFRACTIONr_angle_other_deg1.1181.5827571
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7165436
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.95221.207174
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.64415.017602
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0571525
X-RAY DIFFRACTIONr_chiral_restr0.0550.2455
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023946
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02816
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.9515.121726
X-RAY DIFFRACTIONr_mcbond_other1.955.1191725
X-RAY DIFFRACTIONr_mcangle_it3.2657.6752168
X-RAY DIFFRACTIONr_mcangle_other3.2657.6762169
X-RAY DIFFRACTIONr_scbond_it1.7035.2061759
X-RAY DIFFRACTIONr_scbond_other1.7025.2061760
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.847.7442554
X-RAY DIFFRACTIONr_long_range_B_refined5.10658.9683748
X-RAY DIFFRACTIONr_long_range_B_other5.158.9453740
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.12→2.171 Å
RfactorNum. reflection% reflection
Rfree0.376 98 -
Rwork0.336 1727 -
obs--96.26 %

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