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- PDB-9mjz: Crystal structure of WRN helicase with bound allosteric compound 3 -

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Basic information

Entry
Database: PDB / ID: 9mjz
TitleCrystal structure of WRN helicase with bound allosteric compound 3
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: 1.7 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

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)51,63413
Polymers50,4811
Non-polymers1,15412
Water3,495194
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1930 Å2
ΔGint23 kcal/mol
Surface area19710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.130, 58.067, 131.561
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: 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

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Non-polymers , 6 types, 206 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-A1BL6 / (2-anilino-5-{[4-(trifluoromethyl)phenyl]carbamoyl}-1,3-thiazol-4-yl)acetic acid


Mass: 421.393 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H14F3N3O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 194 / 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: 2.2 Å3/Da / Density % sol: 44.07 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 21-27.5% w/v PEG1500, 0.1 M MMT, pH 5.75-6.25

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.95372 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jul 21, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95372 Å / Relative weight: 1
ReflectionResolution: 1.7→34.87 Å / Num. obs: 49994 / % possible obs: 100 % / Redundancy: 8.3 % / CC1/2: 0.996 / Rsym value: 0.037 / Net I/σ(I): 22.6
Reflection shellResolution: 1.7→1.73 Å / Redundancy: 8.2 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 2456 / CC1/2: 0.699

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Processing

Software
NameVersionClassification
autoPROCdata reduction
XDS(VERSION Jan 31data reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
REFMAC5.8.0267refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→34.87 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.944 / SU B: 3.361 / SU ML: 0.105 / Cross valid method: THROUGHOUT / ESU R: 0.138 / ESU R Free: 0.139 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26144 893 2.1 %RANDOM
Rwork0.20945 ---
obs0.21054 41609 84.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 40.812 Å2
Baniso -1Baniso -2Baniso -3
1-0.95 Å20 Å20 Å2
2---0.27 Å20 Å2
3----0.67 Å2
Refinement stepCycle: LAST / Resolution: 1.7→34.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3366 0 72 194 3632
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0133482
X-RAY DIFFRACTIONr_bond_other_d0.0020.0173278
X-RAY DIFFRACTIONr_angle_refined_deg1.4261.6584710
X-RAY DIFFRACTIONr_angle_other_deg1.2351.5787523
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9365437
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.79422.022178
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.39715585
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.3561523
X-RAY DIFFRACTIONr_chiral_restr0.0690.2455
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.023950
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02808
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_it2.4524.3541712
X-RAY DIFFRACTIONr_mcbond_other2.4524.3531711
X-RAY DIFFRACTIONr_mcangle_it3.4916.5292146
X-RAY DIFFRACTIONr_mcangle_other3.4916.5312147
X-RAY DIFFRACTIONr_scbond_it2.5427.131770
X-RAY DIFFRACTIONr_scbond_other2.5417.1291771
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.80811.4992560
X-RAY DIFFRACTIONr_long_range_B_refined5.5833817
X-RAY DIFFRACTIONr_long_range_B_other5.5693801
X-RAY DIFFRACTIONr_rigid_bond_restr4.90534
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.742 Å
RfactorNum. reflection% reflection
Rfree0.369 69 -
Rwork0.33 3157 -
obs--88.43 %

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