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- PDB-7gqs: Crystal Structure of Werner helicase fragment 517-945 in complex ... -

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Basic information

Entry
Database: PDB / ID: 7gqs
TitleCrystal Structure of Werner helicase fragment 517-945 in complex with ADP
ComponentsBifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
KeywordsHYDROLASE / DNA HELICASE / WERNER SYNDROME / RecQ protein-like 2 / ATP-dependent helicase / Bifunctional 3'-5' exonuclease/ATP-dependent helicase / WRN Werner syndrome protein / RecQ-like type 3
Function / homology
Function and homology information


3'-flap-structured DNA binding / positive regulation of strand invasion / telomeric G-quadruplex DNA binding / forked DNA-dependent helicase activity / 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 / G-quadruplex DNA unwinding ...3'-flap-structured DNA binding / positive regulation of strand invasion / telomeric G-quadruplex DNA binding / forked DNA-dependent helicase activity / 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 / G-quadruplex DNA unwinding / t-circle formation / telomeric D-loop disassembly / Y-form DNA binding / DNA 3'-5' helicase / four-way junction helicase activity / G-quadruplex DNA binding / MutLalpha complex binding / bubble DNA binding / Processive synthesis on the C-strand of the telomere / Impaired BRCA2 binding to PALB2 / Removal of the Flap Intermediate from the C-strand / protein localization to nucleolus / 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 / Homologous DNA Pairing and Strand Exchange / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / 3'-5' DNA helicase activity / response to UV-C / Resolution of D-loop Structures through Holliday Junction Intermediates / exonuclease activity / DNA duplex unwinding / HDR through Single Strand Annealing (SSA) / DNA metabolic process / Impaired BRCA2 binding to RAD51 / DNA synthesis involved in DNA repair / DNA unwinding involved in DNA replication / replication fork processing / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / SUMOylation of DNA damage response and repair proteins / four-way junction DNA binding / 3'-5' exonuclease activity / DNA helicase activity / cellular response to starvation / telomere maintenance / replication fork / determination of adult lifespan / double-strand break repair via homologous recombination / base-excision repair / cellular response to gamma radiation / HDR through Homologous Recombination (HRR) / G2/M DNA damage checkpoint / double-strand break repair / cellular senescence / chromosome / manganese ion binding / Processing of DNA double-strand break ends / response to oxidative stress / Regulation of TP53 Activity through Phosphorylation / DNA replication / chromosome, telomeric region / Hydrolases; Acting on ester bonds / nuclear speck / centrosome / DNA damage response / chromatin binding / protein-containing complex binding / nucleolus / magnesium ion binding / ATP hydrolysis activity / protein homodimerization 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 / ATP-dependent DNA helicase RecQ, zinc-binding domain / RecQ zinc-binding / DNA helicase, ATP-dependent, RecQ type / Helicase and RNase D C-terminal / HRDC domain ...Helicase Helix-turn-helix domain / Helix-turn-helix domain / RQC domain / RQC / RQC domain / ATP-dependent DNA helicase RecQ, zinc-binding domain / RecQ zinc-binding / DNA helicase, ATP-dependent, RecQ type / Helicase and RNase D C-terminal / HRDC domain / HRDC domain / HRDC domain profile. / HRDC domain superfamily / 3'-5' exonuclease / 3'-5' exonuclease / 3'-5' exonuclease domain / HRDC-like superfamily / DEAD/DEAH box helicase / DEAD/DEAH box helicase domain / 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 / Winged helix DNA-binding domain superfamily / Ribonuclease H-like superfamily / Winged helix-like DNA-binding domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / : / Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.57 Å
AuthorsClassen, M. / Benz, J. / Brugger, D. / Rudolph, M.G.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
F. Hoffmann-La Roche LTD Switzerland
CitationJournal: Nature / Year: 2024
Title: Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.
Authors: Baltgalvis, K.A. / Lamb, K.N. / Symons, K.T. / Wu, C.C. / Hoffman, M.A. / Snead, A.N. / Song, X. / Glaza, T. / Kikuchi, S. / Green, J.C. / Rogness, D.C. / Lam, B. / Rodriguez-Aguirre, M.E. / ...Authors: Baltgalvis, K.A. / Lamb, K.N. / Symons, K.T. / Wu, C.C. / Hoffman, M.A. / Snead, A.N. / Song, X. / Glaza, T. / Kikuchi, S. / Green, J.C. / Rogness, D.C. / Lam, B. / Rodriguez-Aguirre, M.E. / Woody, D.R. / Eissler, C.L. / Rodiles, S. / Negron, S.M. / Bernard, S.M. / Tran, E. / Pollock, J. / Tabatabaei, A. / Contreras, V. / Williams, H.N. / Pastuszka, M.K. / Sigler, J.J. / Pettazzoni, P. / Rudolph, M.G. / Classen, M. / Brugger, D. / Claiborne, C. / Plancher, J.M. / Cuartas, I. / Seoane, J. / Burgess, L.E. / Abraham, R.T. / Weinstein, D.S. / Simon, G.M. / Patricelli, M.P. / Kinsella, T.M.
History
DepositionOct 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _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)50,9898
Polymers50,0651
Non-polymers9247
Water4,684260
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, elutes as a monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.071, 90.066, 53.788
Angle α, β, γ (deg.)90.000, 102.460, 90.000
Int Tables number4
Space group name H-MP1211

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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


Mass: 50064.746 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WRN / Plasmid: pFastBac1_hWRN(517-945)_C-H3CV-GFP-10His / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q14191

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Non-polymers , 5 types, 267 molecules

#2: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE / Adenosine diphosphate


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
#3: Chemical ChemComp-CD / CADMIUM ION


Mass: 112.411 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cd
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 260 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.37 Å3/Da / Density % sol: 48 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 5 mg/mL protein in 20mM TRIS/HCl pH7.5, 350mM NaCl, 0.25mM TCEP, 2.5% glycerol mixed 40nL with 180nL reservoir consisting of 9.091 %w/v Silver Bullets 42, 0.091 M MES monohydrate, 2.727 %v/v ...Details: 5 mg/mL protein in 20mM TRIS/HCl pH7.5, 350mM NaCl, 0.25mM TCEP, 2.5% glycerol mixed 40nL with 180nL reservoir consisting of 9.091 %w/v Silver Bullets 42, 0.091 M MES monohydrate, 2.727 %v/v Jeffamine T-403, 13.6 %v/v pentaerythritol ethoxylate, 0.182M Potassium acetate pH6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99997 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 1.57→48.89 Å / Num. obs: 63541 / % possible obs: 98.2 % / Redundancy: 7.036 % / Biso Wilson estimate: 21.12 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.089 / Rrim(I) all: 0.096 / Χ2: 0.819 / Net I/σ(I): 10.47 / Num. measured all: 447065 / Scaling rejects: 141
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.57-1.617.2753.7410.4733667478046280.2164.02596.8
1.61-1.667.253.1560.632511461044840.3063.39797.3
1.66-1.717.1772.5310.7631477452943860.4322.72796.8
1.71-1.767.0511.8821.0330171439842790.5542.03197.3
1.76-1.826.7761.2561.628065424741420.711.36197.5
1.82-1.886.660.9252.2526945414540460.8211.00597.6
1.88-1.957.1490.7672.9327796398438880.8860.82797.6
1.95-2.037.3280.5454.1127496381837520.9390.58698.3
2.03-2.127.2730.3686.0726240366836080.9710.39698.4
2.12-2.227.2040.2787.8824913350634580.9840.398.6
2.22-2.347.0270.2269.9823175335732980.9880.24498.2
2.34-2.496.8260.16912.421364315731300.9920.18399.1
2.49-2.666.4940.12215.7619280299929690.9950.13399
2.66-2.877.1210.09720.5119489275527370.9970.10599.3
2.87-3.147.3140.07226.5418637256925480.9980.07899.2
3.14-3.527.1530.05233.4716487231023050.9990.05799.8
3.52-4.066.8540.04238.3913990205020410.9990.04699.6
4.06-4.976.3560.03741.1911040174117370.9990.0499.8
4.97-7.036.830.0441.899173134613430.9980.04399.8
7.03-48.896.7570.02946.3551497687620.9990.03299.2

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHENIXdev_4357refinement
PDB_EXTRACT3.28data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 1.57→48.89 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.47 / Phase error: 28.63 / Stereochemistry target values: ML
Details: ADP, no Mg2+, but partial replacement of zinc ions by Cd2+ from Hampton Silver Bullet additive
RfactorNum. reflection% reflectionSelection details
Rfree0.2185 2115 5.05 %RANDOM
Rwork0.1754 39793 --
obs0.1776 41908 65.11 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 126.7 Å2 / Biso mean: 36.3662 Å2 / Biso min: 11.2 Å2
Refinement stepCycle: final / Resolution: 1.57→48.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3382 0 39 260 3681
Biso mean--41.79 37.43 -
Num. residues----425
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.57-1.610.1475130.25572412546
1.61-1.650.2754380.253365469216
1.65-1.70.2921530.2511053110626
1.7-1.750.2677650.25381370143534
1.75-1.80.2658920.25051724181642
1.8-1.870.28851050.23852087219251
1.87-1.940.24831270.23372408253559
1.94-2.030.25671640.20872928309272
2.03-2.140.28962010.20063421362284
2.14-2.270.24521720.19083744391692
2.27-2.450.23662280.18313900412896
2.45-2.690.21882130.18354006421998
2.69-3.080.21882090.18344033424299
3.08-3.880.20982260.160540794305100
3.88-48.890.17692090.142941454354100
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)
12.6679-0.0593-0.11474.6556-0.77042.3175-0.13240.15140.1365-0.36090.18920.3410.0606-0.3744-0.01150.2575-0.1045-0.03470.1763-0.01710.093-5.9198-4.6417-25.0673
23.68811.64120.5053.1216-0.01822.21860.0138-0.0658-0.07310.03690.10090.49690.2695-0.5287-0.12320.2017-0.02730.01060.15530.01050.158-8.2993-12.036-13.2496
30.59-0.51910.25413.262-0.04683.16210.0305-0.00830.0981-0.1738-0.0141-0.0533-0.31090.01150.00180.0336-0.01560.03220.1205-0.01210.13219.340215.6833-7.7673
41.04080.7763-0.34594.59980.9224.59020.0984-0.0572-0.22130.6235-0.02350.05460.6996-0.2564-0.01110.1199-0.006-0.02130.1770.02170.15049.1723-0.76923.7522
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 528 through 681 )A528 - 681
2X-RAY DIFFRACTION2chain 'A' and (resid 682 through 734 )A682 - 734
3X-RAY DIFFRACTION3chain 'A' and (resid 735 through 854 )A735 - 854
4X-RAY DIFFRACTION4chain 'A' and (resid 855 through 952 )A855 - 952

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