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- PDB-10ak: Crystal Structure of Human WRN helicase with compound 4 -

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Basic information

Entry
Database: PDB / ID: 10ak
TitleCrystal Structure of Human WRN helicase with compound 4
ComponentsBifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / DNA HELICASE / RecQ Family / Allosteric Inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
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 / DNA geometric change / telomere maintenance via semi-conservative replication ...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 / DNA geometric change / telomere maintenance via semi-conservative replication / Y-form DNA binding / telomeric D-loop disassembly / four-way junction helicase activity / t-circle formation / 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 / HDR through Single Strand Annealing (SSA) / DNA metabolic process / 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 / DNA synthesis involved in DNA repair / Impaired BRCA2 binding to RAD51 / 3'-5' DNA helicase activity / DNA 3'-5' helicase / replication fork processing / replicative senescence / Presynaptic phase of homologous DNA pairing and strand exchange / mismatch repair / SUMOylation of DNA damage response and repair proteins / four-way junction DNA binding / 3'-5' exonuclease activity / telomere maintenance / cellular response to starvation / DNA helicase activity / replication fork / determination of adult lifespan / cellular response to gamma radiation / G2/M DNA damage checkpoint / base-excision repair / double-strand break repair via homologous recombination / HDR through Homologous Recombination (HRR) / cellular senescence / manganese ion binding / double-strand break repair / 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 / 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: 1.37 Å
AuthorsToms, A.V. / Caravella, J.A. / Sitnikov, N. / Bartels, F. / Svensson, R. / Jacques O'Hagan, S. / Borthwick, J. / Yin, Y. / Zhoa, X. / Li, L. ...Toms, A.V. / Caravella, J.A. / Sitnikov, N. / Bartels, F. / Svensson, R. / Jacques O'Hagan, S. / Borthwick, J. / Yin, Y. / Zhoa, X. / Li, L. / Liu, R. / Talbot, E. / Kong, H. / Freund, R.R.A. / Browning, B. / Genung, N. / Carreiro, S. / Brennan, D. / Graves, A.P. / Loh, C. / Tummino, P. / Edmondson, S.D. / Li, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2026
Title: Design of Cyclic Vinyl Sulfones as WRN Covalent Inhibitors from Noncovalent Binders.
Authors: Caravella, J.A. / Toms, A.V. / Sitnikov, N. / Bartels, F. / Svensson, R. / O'Hagan, S.J. / Borthwick, J.A. / Campos, S. / Yin, Y. / Zhao, X. / Li, L. / Liu, R. / Talbot, E. / Kong, H. / ...Authors: Caravella, J.A. / Toms, A.V. / Sitnikov, N. / Bartels, F. / Svensson, R. / O'Hagan, S.J. / Borthwick, J.A. / Campos, S. / Yin, Y. / Zhao, X. / Li, L. / Liu, R. / Talbot, E. / Kong, H. / Adolf Freund, R.R. / Browning, B. / Genung, N.E. / Carreiro, S. / Brennan, D. / Graves, A.P. / Loh, C. / Tummino, P. / Edmondson, S.D. / Li, D.
History
DepositionJan 8, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)49,9009
Polymers49,1071
Non-polymers7938
Water8,269459
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.293, 58.216, 131.619
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 49106.613 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WRN, RECQ3, RECQL2 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q14191, Hydrolases; Acting on ester bonds, DNA 3'-5' helicase

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Non-polymers , 5 types, 467 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-A1C4L / N-benzyl-N-[(3R)-1,1-dioxo-1lambda~6~-thiolan-3-yl]-2-[4-(1H-pyrrol-1-yl)phenyl]acetamide / N-benzyl-N-[(3R)-1,1-dioxo-2,3-dihydro-1H-1lambda~6~-thiophen-3-yl]-2-[4-(1H-pyrrol-1-yl)phenyl]acetamide bound form


Mass: 408.513 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24N2O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 459 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.32 Å3/Da / Density % sol: 47.12 %
Crystal growTemperature: 290 K / Method: vapor diffusion
Details: protocol was established using PROTEROS Standard Protocols

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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: Apr 7, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.368→65.81 Å / Num. obs: 95235 / % possible obs: 100 % / Redundancy: 8.1 % / Rmerge(I) obs: 0.05 / Rsym value: 0.05 / Net I/σ(I): 18
Reflection shellResolution: 1.368→1.392 Å / Redundancy: 7.5 % / Rmerge(I) obs: 1.308 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 4732 / Rsym value: 1.308 / % possible all: 100

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION Jan 31data reduction
autoPROCdata reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
REFMAC5.8.0049refinement
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.37→65.81 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.962 / SU B: 1.337 / SU ML: 0.053 / Cross valid method: THROUGHOUT / ESU R: 0.068 / ESU R Free: 0.065 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21414 4433 4.9 %RANDOM
Rwork0.20313 ---
obs0.2037 86011 94.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.074 Å2
Baniso -1Baniso -2Baniso -3
1-0.37 Å2-0 Å2-0 Å2
2---0.39 Å2-0 Å2
3---0.02 Å2
Refinement stepCycle: LAST / Resolution: 1.37→65.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3372 0 48 459 3879
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0193553
X-RAY DIFFRACTIONr_bond_other_d0.0020.023422
X-RAY DIFFRACTIONr_angle_refined_deg1.3261.9754826
X-RAY DIFFRACTIONr_angle_other_deg1.1537888
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6085453
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.92523.438160
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.66715.122656
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.891526
X-RAY DIFFRACTIONr_chiral_restr0.0750.2538
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213999
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02825
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_it0.8952.3221726
X-RAY DIFFRACTIONr_mcbond_other0.8942.3211725
X-RAY DIFFRACTIONr_mcangle_it1.5623.4792162
X-RAY DIFFRACTIONr_mcangle_other1.5623.482163
X-RAY DIFFRACTIONr_scbond_it1.0122.4241827
X-RAY DIFFRACTIONr_scbond_other1.0122.4241827
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.6833.5812643
X-RAY DIFFRACTIONr_long_range_B_refined4.55519.7164346
X-RAY DIFFRACTIONr_long_range_B_other4.15518.84096
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.37→1.404 Å
RfactorNum. reflection% reflection
Rfree0.333 305 -
Rwork0.332 6218 -
obs--93.71 %

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