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- PDB-4luo: Fragment-Based Discovery of a Potent Inhibitor of Replication Pro... -

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Basic information

Entry
Database: PDB / ID: 4luo
TitleFragment-Based Discovery of a Potent Inhibitor of Replication Protein A Protein-Protein Interactions
ComponentsReplication protein A 70 kDa DNA-binding subunitDNA replication
KeywordsPROTEIN BINDING / OB-FOLD / PROTEIN-PROTEIN INTERACTION
Function / homology
Function and homology information


protein localization to chromosome / DNA replication factor A complex / chromatin-protein adaptor activity / protein localization to site of double-strand break / Removal of the Flap Intermediate / G-rich strand telomeric DNA binding / Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) / Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) / single-stranded telomeric DNA binding / Removal of the Flap Intermediate from the C-strand ...protein localization to chromosome / DNA replication factor A complex / chromatin-protein adaptor activity / protein localization to site of double-strand break / Removal of the Flap Intermediate / G-rich strand telomeric DNA binding / Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) / Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) / single-stranded telomeric DNA binding / Removal of the Flap Intermediate from the C-strand / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / site of DNA damage / Presynaptic phase of homologous DNA pairing and strand exchange / telomere maintenance via telomerase / PCNA-Dependent Long Patch Base Excision Repair / mismatch repair / Activation of the pre-replicative complex / HSF1 activation / Regulation of HSF1-mediated heat shock response / Activation of ATR in response to replication stress / SUMOylation of DNA damage response and repair proteins / telomere maintenance / Translesion synthesis by REV1 / Translesion synthesis by POLK / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / meiotic cell cycle / Recognition of DNA damage by PCNA-containing replication complex / nucleotide-excision repair / Fanconi Anemia Pathway / Termination of translesion DNA synthesis / double-strand break repair via homologous recombination / Translesion Synthesis by POLH / HDR through Homologous Recombination (HRR) / Dual Incision in GG-NER / G2/M DNA damage checkpoint / base-excision repair / DNA-templated DNA replication / PML body / Formation of Incision Complex in GG-NER / Meiotic recombination / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / single-stranded DNA binding / site of double-strand break / Processing of DNA double-strand break ends / DNA recombination / Regulation of TP53 Activity through Phosphorylation / DNA replication / chromosome, telomeric region / damaged DNA binding / DNA repair / DNA damage response / nucleoplasm / metal ion binding / nucleus
Similarity search - Function
Replication factor-A protein 1, N-terminal domain / Replication factor A protein 1 / Replication factor-A protein 1, N-terminal / Replication protein A, OB domain / Replication protein A OB domain / : / Replication factor A, C-terminal / Replication factor-A C terminal domain / OB-fold nucleic acid binding domain, AA-tRNA synthetase-type / OB-fold nucleic acid binding domain ...Replication factor-A protein 1, N-terminal domain / Replication factor A protein 1 / Replication factor-A protein 1, N-terminal / Replication protein A, OB domain / Replication protein A OB domain / : / Replication factor A, C-terminal / Replication factor-A C terminal domain / OB-fold nucleic acid binding domain, AA-tRNA synthetase-type / OB-fold nucleic acid binding domain / Nucleic acid-binding proteins / OB fold (Dihydrolipoamide Acetyltransferase, E2P) / Nucleic acid-binding, OB-fold / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-1DZ / Replication protein A 70 kDa DNA-binding subunit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.54 Å
AuthorsFeldkamp, M.D. / Frank, A.O. / Kennedy, J.P. / Waterson, A.G. / Olejniczak, E.T. / Pelz, N.F. / Patrone, J.D. / Vangamudi, B. / Camper, D.V. / Rossanese, O.W. ...Feldkamp, M.D. / Frank, A.O. / Kennedy, J.P. / Waterson, A.G. / Olejniczak, E.T. / Pelz, N.F. / Patrone, J.D. / Vangamudi, B. / Camper, D.V. / Rossanese, O.W. / Fesik, S.W. / Chazin, W.J.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach.
Authors: Frank, A.O. / Feldkamp, M.D. / Kennedy, J.P. / Waterson, A.G. / Pelz, N.F. / Patrone, J.D. / Vangamudi, B. / Camper, D.V. / Rossanese, O.W. / Chazin, W.J. / Fesik, S.W.
History
DepositionJul 25, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2014Group: Database references
Revision 1.2Nov 12, 2014Group: Structure summary
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Replication protein A 70 kDa DNA-binding subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,0543
Polymers13,4981
Non-polymers5572
Water1,67593
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.308, 53.022, 53.829
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 Replication protein A 70 kDa DNA-binding subunit / DNA replication / RP-A p70 / Replication factor A protein 1 / RF-A protein 1 / Single-stranded DNA-binding protein / ...RP-A p70 / Replication factor A protein 1 / RF-A protein 1 / Single-stranded DNA-binding protein / Replication protein A 70 kDa DNA-binding subunit / N-terminally processed


Mass: 13497.728 Da / Num. of mol.: 1 / Fragment: RPA70N (unp residues 1-120) / Mutation: E7R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RPA1, REPA1, RPA70 / Plasmid: PET15B / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-DE3 / References: UniProt: P27694
#2: Chemical ChemComp-1DZ / 1-(3-methylphenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid


Mass: 278.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H14N2O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 93 / Source method: isolated from a natural source / Formula: H2O

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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: 2.03 Å3/Da / Density % sol: 39.26 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100 MM MES, 200 MM CALCIUM ACETATE, 20% PEG 8000, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 294K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 12, 2013
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.54→31.211 Å / Num. all: 418133 / Num. obs: 31399 / % possible obs: 99.91 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.111
Reflection shellResolution: 1.54→1.57 Å / Redundancy: 9.6 % / Rmerge(I) obs: 0.72 / Mean I/σ(I) obs: 5.35 / Num. unique all: 820 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHENIX(phenix.refine: 1.8.2_1309)model building
PHENIX(phenix.refine: 1.8.2_1309)refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHENIX1.8.2_1309phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2B29
Resolution: 1.54→31.211 Å / SU ML: 0.15 / σ(F): 1.33 / Phase error: 19.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1893 847 5.06 %Random
Rwork0.1706 ---
obs0.1716 16741 99.55 %-
Solvent computationShrinkage radii: 0.7 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.54→31.211 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms930 0 42 93 1065
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071094
X-RAY DIFFRACTIONf_angle_d1.3831505
X-RAY DIFFRACTIONf_dihedral_angle_d16.062426
X-RAY DIFFRACTIONf_chiral_restr0.071180
X-RAY DIFFRACTIONf_plane_restr0.005194
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5391-1.63550.24991530.2112535X-RAY DIFFRACTION98
1.6355-1.76180.23471400.19222618X-RAY DIFFRACTION100
1.7618-1.93910.26041320.16712622X-RAY DIFFRACTION100
1.9391-2.21960.17921470.15142634X-RAY DIFFRACTION100
2.2196-2.79620.17341400.17382679X-RAY DIFFRACTION100
2.7962-31.21760.17461350.16942806X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
16.89831.6781-2.70164.1354-0.29862.35390.01440.04430.24330.05680.06530.15120.0502-0.5926-0.04270.0992-0.0029-0.00330.1276-0.00450.15613.80491.5449-4.6245
22.038-0.66530.57833.13490.65122.6654-0.09410.23060.1303-0.31950.0676-0.1387-0.20690.2379-0.00260.142-0.01960.01240.14930.02370.11328.062-5.4107-10.2171
31.8725-0.01742.73273.3173-2.51535.85670.4121.423-0.7838-1.67510.013-0.90060.25950.5205-0.25370.39920.02360.08160.4411-0.13780.37199.8594-21.2696-22.1619
41.9337-1.3872-0.44713.17770.67671.19150.035-0.0063-0.0239-0.03160.0398-0.07490.03690.0586-0.09230.1108-0.0182-0.01710.13140.00020.11617.1581-13.2228-10.0216
50.51620.04050.11781.7747-2.52818.5666-0.04110.10060.0149-0.1659-0.0426-0.04040.22320.39430.07720.1433-0.02080.00610.1560.02040.162511.8067-5.4329-16.3297
62.81040.6578-0.63531.8493-1.49727.7303-0.07970.0546-0.0657-0.07340.0352-0.06430.00810.23490.04840.1489-0.01270.00960.13440.01590.152912.7069-8.2125-11.1513
73.4471-1.18190.80496.1842-5.41368.37010.07370.0207-0.0018-0.01980.22790.38580.0109-0.2943-0.30140.1163-0.02380.00490.1398-0.01080.1739-2.0377-5.9275-5.6138
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -2 through 15 )
2X-RAY DIFFRACTION2chain 'A' and (resid 16 through 32 )
3X-RAY DIFFRACTION3chain 'A' and (resid 33 through 41 )
4X-RAY DIFFRACTION4chain 'A' and (resid 42 through 75 )
5X-RAY DIFFRACTION5chain 'A' and (resid 76 through 91 )
6X-RAY DIFFRACTION6chain 'A' and (resid 92 through 103 )
7X-RAY DIFFRACTION7chain 'A' and (resid 104 through 120 )

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