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- PDB-8br9: Stapled peptide SP24 in complex with humanised RadA mutant HumRadA22 -

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Basic information

Entry
Database: PDB / ID: 8br9
TitleStapled peptide SP24 in complex with humanised RadA mutant HumRadA22
Components
  • Breast cancer type 2 susceptibility protein
  • DNA repair and recombination protein RadA
KeywordsRECOMBINATION / Stapled peptide / Rad51 / BRCA2 / BRC repeat
Function / homology
Function and homology information


BRCA2-MAGE-D1 complex / negative regulation of mammary gland epithelial cell proliferation / mitotic recombination-dependent replication fork processing / establishment of protein localization to telomere / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / nuclear ubiquitin ligase complex / histone H4 acetyltransferase activity / histone H3 acetyltransferase activity / lateral element ...BRCA2-MAGE-D1 complex / negative regulation of mammary gland epithelial cell proliferation / mitotic recombination-dependent replication fork processing / establishment of protein localization to telomere / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / nuclear ubiquitin ligase complex / histone H4 acetyltransferase activity / histone H3 acetyltransferase activity / lateral element / telomere maintenance via recombination / regulation of DNA damage checkpoint / oocyte maturation / Impaired BRCA2 binding to PALB2 / HDR through MMEJ (alt-NHEJ) / gamma-tubulin binding / DNA repair complex / 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) / response to UV-C / Resolution of D-loop Structures through Holliday Junction Intermediates / inner cell mass cell proliferation / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / hematopoietic stem cell proliferation / ATP-dependent DNA damage sensor activity / Impaired BRCA2 binding to RAD51 / female gonad development / male meiosis I / Presynaptic phase of homologous DNA pairing and strand exchange / centrosome duplication / response to X-ray / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of mitotic cell cycle / regulation of cytokinesis / secretory granule / cellular response to ionizing radiation / nucleotide-excision repair / response to gamma radiation / double-strand break repair via homologous recombination / brain development / HDR through Homologous Recombination (HRR) / Meiotic recombination / double-strand break repair / cellular senescence / single-stranded DNA binding / spermatogenesis / DNA recombination / protease binding / chromosome, telomeric region / damaged DNA binding / DNA repair / centrosome / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / ATP hydrolysis activity / protein-containing complex / nucleoplasm / ATP binding / identical protein binding / nucleus / cytosol
Similarity search - Function
: / BRCA2, OB2 / BRCA2, OB3 / Tower domain / Breast cancer type 2 susceptibility protein, helical domain / BRCA2 helical domain superfamily / BRCA2, oligonucleotide/oligosaccharide-binding, domain 3 / Tower / BRCA2, helical / Tower ...: / BRCA2, OB2 / BRCA2, OB3 / Tower domain / Breast cancer type 2 susceptibility protein, helical domain / BRCA2 helical domain superfamily / BRCA2, oligonucleotide/oligosaccharide-binding, domain 3 / Tower / BRCA2, helical / Tower / BRCA2 repeat / BRCA2, OB1 / Breast cancer type 2 susceptibility protein / BRCA2 repeat / BRCA2, oligonucleotide/oligosaccharide-binding, domain 1 / BRCA2 repeat profile. / DNA recombination/repair protein RadA / DNA recombination and repair protein, RecA-like / DNA recombination and repair protein Rad51-like, C-terminal / Rad51 / DNA recombination and repair protein RecA, monomer-monomer interface / RecA family profile 2. / DNA recombination and repair protein RecA-like, ATP-binding domain / RecA family profile 1. / DNA repair Rad51/transcription factor NusA, alpha-helical / Helix-hairpin-helix domain / Helix-hairpin-helix DNA-binding motif, class 1 / Helix-hairpin-helix DNA-binding motif class 1 / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Nucleic acid-binding, OB-fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / 4,6-diethylpyrimidin-2-amine / DNA repair and recombination protein RadA / Breast cancer type 2 susceptibility protein
Similarity search - Component
Biological speciesPyrococcus furiosus (archaea)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.63 Å
AuthorsPantelejevs, T. / Hyvonen, M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)DTP United Kingdom
Citation
Journal: Chem Sci / Year: 2023
Title: A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase.
Authors: Pantelejevs, T. / Zuazua-Villar, P. / Koczy, O. / Counsell, A.J. / Walsh, S.J. / Robertson, N.S. / Spring, D.R. / Downs, J.A. / Hyvonen, M.
#1: Journal: Biorxiv / Year: 2023
Title: A Recombinant Approach For Stapled Peptide Discovery Yields Inhibitors of the RAD51 Recombinase
Authors: Pantelejevs, T. / Zuazua-Villar, P. / Koczy, O. / Counsell, A. / Walsh, S.J. / Robertson, N.S. / Spring, D.R. / Downs, J. / Hyvonen, M.
History
DepositionNov 22, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Revision 1.2Feb 7, 2024Group: Refinement description / Category: pdbx_initial_refinement_model
Item: _pdbx_initial_refinement_model.accession_code / _pdbx_initial_refinement_model.source_name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA repair and recombination protein RadA
B: Breast cancer type 2 susceptibility protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,1064
Polymers29,5282
Non-polymers5782
Water1,47782
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2290 Å2
ΔGint-20 kcal/mol
Surface area11250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)140.464, 38.642, 43.528
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z
Components on special symmetry positions
IDModelComponents
11A-521-

HOH

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Components

#1: Protein DNA repair and recombination protein RadA / Humanised RadA mutant HumRadA22


Mass: 25542.064 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Pyrococcus furiosus (archaea) / Gene: radA, PF1926 / Production host: Escherichia coli (E. coli) / References: UniProt: O74036
#2: Protein/peptide Breast cancer type 2 susceptibility protein / Fanconi anemia group D1 protein


Mass: 3985.500 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRCA2, FACD, FANCD1 / Production host: Escherichia coli (E. coli) / References: UniProt: P51587
#3: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE / Adenosine diphosphate


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#4: Chemical ChemComp-RF6 / 4,6-diethylpyrimidin-2-amine / 4,6-bis(ethenyl)pyrimidin-2-amine (precursor) / 4,6-Divinylpyrimidin-2-amine (precursor) / peptide staple


Mass: 151.209 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H13N3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 82 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.3 Å3/Da / Density % sol: 46.53 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Na 3 Cit 4.2 pH (Buffer) 20 %w/v PEG 1K (Precipitant) 0.2 M Li 2 SO4 (Salt)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jan 19, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.63→70.23 Å / Num. obs: 30303 / % possible obs: 98.7 % / Redundancy: 7.9 % / Biso Wilson estimate: 39.72 Å2 / CC1/2: 1 / Rrim(I) all: 0.059 / Net I/σ(I): 12
Reflection shellResolution: 1.63→1.66 Å / Mean I/σ(I) obs: 0.3 / Num. unique obs: 11733 / CC1/2: 0.3

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Processing

Software
NameVersionClassification
BUSTERrefinement
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6HQU

6hqu


Resolution: 1.63→43.53 Å / SU ML: 0.321 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 41.9146
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2816 1444 4.93 %
Rwork0.25 27833 -
obs0.2515 29277 95.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.1 Å2
Refinement stepCycle: LAST / Resolution: 1.63→43.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1854 0 38 82 1974
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01271925
X-RAY DIFFRACTIONf_angle_d1.60362592
X-RAY DIFFRACTIONf_chiral_restr0.1002290
X-RAY DIFFRACTIONf_plane_restr0.0058341
X-RAY DIFFRACTIONf_dihedral_angle_d15.1536727
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.63-1.690.51551160.54171980X-RAY DIFFRACTION69.27
1.69-1.750.48141630.47382729X-RAY DIFFRACTION96.08
1.75-1.830.50791470.4582792X-RAY DIFFRACTION97.64
1.83-1.930.37511250.37342838X-RAY DIFFRACTION97.72
1.93-2.050.3521370.29372830X-RAY DIFFRACTION98.15
2.05-2.210.3261460.29712832X-RAY DIFFRACTION98.32
2.21-2.430.29351660.27552873X-RAY DIFFRACTION98.16
2.43-2.780.3031410.26752900X-RAY DIFFRACTION99.35
2.78-3.50.27841630.24792936X-RAY DIFFRACTION99.49
3.5-43.530.23931400.21213123X-RAY DIFFRACTION99.36
Refinement TLS params.Method: refined / Origin x: 19.2704162755 Å / Origin y: -26.3070323133 Å / Origin z: 1.8340566476 Å
111213212223313233
T0.42616890283 Å2-0.0488729083112 Å2-0.0257259511287 Å2-0.308521290065 Å20.0142291589933 Å2--0.254209943153 Å2
L3.08112648419 °20.755830455827 °20.344779557802 °2-2.09394124151 °2-0.822674024317 °2--6.07610517046 °2
S-0.180404119604 Å °-0.139648616588 Å °-0.0458727849536 Å °-0.0171782837694 Å °-0.00290564937696 Å °-0.000650007875594 Å °-0.206260341813 Å °0.151575495579 Å °0.179819811271 Å °
Refinement TLS groupSelection details: {A|* B|*}

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