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- PDB-4lw1: Fragment-Based Discovery of a Potent Inhibitor of Replication Pro... -

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Basic information

Entry
Database: PDB / ID: 4lw1
TitleFragment-Based Discovery of a Potent Inhibitor of Replication Protein A Protein-Protein Interactions
ComponentsReplication protein A 70 kDa DNA-binding subunit
KeywordsDNA BINDING protein/inhibitor / OB-FOLD / PROTEIN-PROTEIN INTERACTION / DNA BINDING protein-inhibitor complex
Function / homology
Function and homology information


protein localization to chromosome / DNA replication factor A complex / lateral element / single-stranded telomeric DNA binding / G-rich strand telomeric DNA binding / Removal of the Flap Intermediate / chromatin-protein adaptor activity / protein localization to site of double-strand break / Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) / Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) ...protein localization to chromosome / DNA replication factor A complex / lateral element / single-stranded telomeric DNA binding / G-rich strand telomeric DNA binding / Removal of the Flap Intermediate / chromatin-protein adaptor activity / protein localization to site of double-strand break / Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) / Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) / Removal of the Flap Intermediate from the C-strand / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / hemopoiesis / Presynaptic phase of homologous DNA pairing and strand exchange / site of DNA damage / PCNA-Dependent Long Patch Base Excision Repair / Regulation of HSF1-mediated heat shock response / Activation of the pre-replicative complex / HSF1 activation / telomere maintenance via telomerase / mismatch repair / Activation of ATR in response to replication stress / SUMOylation of DNA damage response and repair proteins / homeostasis of number of cells within a tissue / 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 / male germ cell nucleus / nucleotide-excision repair / Fanconi Anemia Pathway / Termination of translesion DNA synthesis / Recognition of DNA damage by PCNA-containing replication complex / Translesion Synthesis by POLH / double-strand break repair via homologous recombination / base-excision repair / PML body / G2/M DNA damage checkpoint / HDR through Homologous Recombination (HRR) / Dual Incision in GG-NER / Meiotic recombination / DNA-templated DNA replication / Formation of Incision Complex in GG-NER / 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 / in utero embryonic development / damaged DNA binding / chromosome, telomeric region / DNA replication / DNA repair / positive regulation of cell population proliferation / DNA damage response / chromatin binding / zinc ion binding / nucleoplasm / 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-1XS / Replication protein A 70 kDa DNA-binding subunit
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.631 Å
AuthorsFeldkamp, M.D. / Frank, A.O. / Kennedy, J.P. / Waterson, A.G. / Olejnczak, E.O. / 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. / Olejnczak, E.O. / 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 26, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2014Group: Database references
Revision 1.2Dec 10, 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)13,9793
Polymers13,4981
Non-polymers4812
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.166, 53.527, 54.117
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 / 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-1XS / 5-(3-chloro-4-fluorophenyl)furan-2-carboxylic acid


Mass: 240.615 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H6ClFO3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / 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: 2.05 Å3/Da / Density % sol: 39.93 %
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: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Oct 7, 2011 / Details: SI(111)
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.63→50 Å / Num. all: 223817 / Num. obs: 14364 / % possible obs: 99.64 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 20.66 Å2 / Rmerge(I) obs: 0.082 / Net I/σ(I): 18.96
Reflection shellResolution: 1.63→1.69 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.595 / Mean I/σ(I) obs: 3.51 / Num. unique all: 1406 / % possible all: 97.18

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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
HKL-2000data scaling
PHENIX1.8.2_1309phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2B29

2b29


Resolution: 1.631→31.19 Å / SU ML: 0.15 / σ(F): 1.35 / Phase error: 19.94 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2097 720 5.03 %RANDOM
Rwork0.1784 ---
obs0.1799 14313 99.63 %-
all-223817 --
Solvent computationShrinkage radii: 0.7 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.631→31.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms937 0 32 71 1040
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081103
X-RAY DIFFRACTIONf_angle_d1.3711516
X-RAY DIFFRACTIONf_dihedral_angle_d20.2450
X-RAY DIFFRACTIONf_chiral_restr0.091178
X-RAY DIFFRACTIONf_plane_restr0.007199
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.631-1.75690.26861590.21932611X-RAY DIFFRACTION98
1.7569-1.93370.20651460.18492686X-RAY DIFFRACTION100
1.9337-2.21340.20511400.16512692X-RAY DIFFRACTION100
2.2134-2.78840.23721370.18952732X-RAY DIFFRACTION100
2.7884-31.19540.19181380.17182872X-RAY DIFFRACTION100
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)
19.173-0.8331-3.38386.067-1.53595.2509-0.0238-0.02680.4443-0.0069-0.0168-0.1631-0.31130.29720.11170.09330.0196-0.0550.1411-0.00480.1949-3.72451.14925.2149
27.90220.6677-1.42885.4518-2.85388.5199-0.3901-1.44481.17031.55960.15351.063-1.2776-0.87190.28070.45190.18970.04160.4371-0.10310.4263-15.23472.930410.7663
33.03571.9933-2.71393.7391-4.2584.9548-0.1058-0.2859-0.1990.6599-0.3258-0.4665-0.14040.33980.45090.18530.007-0.03590.1587-0.00450.1281-2.9695-12.463310.833
44.0134.75684.5978.84793.42016.54931.3488-2.1153-1.55871.9832-0.25870.54091.7479-0.6895-1.06640.5738-0.0778-0.06340.75470.15250.5189-10.6126-23.204223.2099
54.69174.07250.06835.9750.33671.58620.2141-0.36910.03570.3213-0.11560.06370.0069-0.0588-0.11290.13880.0288-0.00730.17760.00830.1196-7.2404-11.9512.7811
65.25795.6128-2.46086.1997-2.62041.30040.1176-0.32780.05760.2150.04250.10240.1614-0.0602-0.16410.19990.0141-0.04130.20610.00250.1598-6.7604-18.47484.1179
70.323-0.1805-0.18242.46352.70022.92730.0027-0.06450.03750.1496-0.06160.0270.2271-0.35540.04660.12610.02640.00820.2105-0.01360.1725-11.8171-5.425516.7872
82.9616-0.7959-0.4073.73634.37718.72590.0030.0004-0.00970.1728-0.19170.1410.0561-0.83410.15040.12420.00860.01530.1584-0.00030.1358-12.8355-8.436810.4846
94.6461-0.30660.1348.03694.8195.62390.0928-0.35490.35020.3826-0.1376-0.05410.30610.1586-0.04160.1304-0.02150.01840.1872-0.01490.16481.8058-5.54686.6095
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 23 )
3X-RAY DIFFRACTION3chain 'A' and (resid 24 through 33 )
4X-RAY DIFFRACTION4chain 'A' and (resid 34 through 40 )
5X-RAY DIFFRACTION5chain 'A' and (resid 41 through 67 )
6X-RAY DIFFRACTION6chain 'A' and (resid 68 through 75 )
7X-RAY DIFFRACTION7chain 'A' and (resid 76 through 91 )
8X-RAY DIFFRACTION8chain 'A' and (resid 92 through 103 )
9X-RAY DIFFRACTION9chain 'A' and (resid 104 through 120 )

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