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- PDB-6wh2: Structure of the C-terminal BRCT domain of human XRCC1 -

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Basic information

Entry
Database: PDB / ID: 6wh2
TitleStructure of the C-terminal BRCT domain of human XRCC1
ComponentsX-ray repair cross complementing protein 1 variant
KeywordsDNA BINDING PROTEIN / DNA ligase complex / DNA repair
Function / homology
Function and homology information


3' overhang single-stranded DNA endodeoxyribonuclease activity / oxidized DNA binding / telomeric DNA-containing double minutes formation / ERCC4-ERCC1 complex / negative regulation of protection from non-homologous end joining at telomere / ADP-D-ribose modification-dependent protein binding / negative regulation of protein ADP-ribosylation / poly-ADP-D-ribose binding / regulation of base-excision repair / single strand break repair ...3' overhang single-stranded DNA endodeoxyribonuclease activity / oxidized DNA binding / telomeric DNA-containing double minutes formation / ERCC4-ERCC1 complex / negative regulation of protection from non-homologous end joining at telomere / ADP-D-ribose modification-dependent protein binding / negative regulation of protein ADP-ribosylation / poly-ADP-D-ribose binding / regulation of base-excision repair / single strand break repair / HDR through MMEJ (alt-NHEJ) / response to hydroperoxide / Resolution of AP sites via the single-nucleotide replacement pathway / APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway / site of DNA damage / Gap-filling DNA repair synthesis and ligation in GG-NER / hippocampus development / base-excision repair / Gap-filling DNA repair synthesis and ligation in TC-NER / double-strand break repair via nonhomologous end joining / double-strand break repair / damaged DNA binding / chromosome, telomeric region / chromatin / nucleolus / enzyme binding / nucleoplasm / nucleus
Similarity search - Function
DNA-repair protein Xrcc1, N-terminal / XRCC1, first (central) BRCT domain / XRCC1 N terminal domain / BRCT domain / BRCA1 C Terminus (BRCT) domain / breast cancer carboxy-terminal domain / BRCT domain profile. / BRCT domain / BRCT domain superfamily / Galactose-binding-like domain superfamily
Similarity search - Domain/homology
DNA repair protein XRCC1 / X-ray repair cross complementing protein 1 variant
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.414 Å
AuthorsPourfarjam, Y. / Ellenberger, T. / Tainer, J.A. / Tomkinson, A.E. / Kim, I.K.
Funding support United States, 1items
OrganizationGrant numberCountry
American Cancer Society133405-RSG-19-200-01-DMC United States
CitationJournal: Nucleic Acids Res / Year: 2021
Title: An atypical BRCT-BRCT interaction with the XRCC1 scaffold protein compacts human DNA Ligase IIIα within a flexible DNA repair complex.
Authors: Michal Hammel / Ishtiaque Rashid / Aleksandr Sverzhinsky / Yasin Pourfarjam / Miaw-Sheue Tsai / Tom Ellenberger / John M Pascal / In-Kwon Kim / John A Tainer / Alan E Tomkinson /
Abstract: The XRCC1-DNA ligase IIIα complex (XL) is critical for DNA single-strand break repair, a key target for PARP inhibitors in cancer cells deficient in homologous recombination. Here, we combined ...The XRCC1-DNA ligase IIIα complex (XL) is critical for DNA single-strand break repair, a key target for PARP inhibitors in cancer cells deficient in homologous recombination. Here, we combined biophysical approaches to gain insights into the shape and conformational flexibility of the XL as well as XRCC1 and DNA ligase IIIα (LigIIIα) alone. Structurally-guided mutational analyses based on the crystal structure of the human BRCT-BRCT heterodimer identified the network of salt bridges that together with the N-terminal extension of the XRCC1 C-terminal BRCT domain constitute the XL molecular interface. Coupling size exclusion chromatography with small angle X-ray scattering and multiangle light scattering (SEC-SAXS-MALS), we determined that the XL is more compact than either XRCC1 or LigIIIα, both of which form transient homodimers and are highly disordered. The reduced disorder and flexibility allowed us to build models of XL particles visualized by negative stain electron microscopy that predict close spatial organization between the LigIIIα catalytic core and both BRCT domains of XRCC1. Together our results identify an atypical BRCT-BRCT interaction as the stable nucleating core of the XL that links the flexible nick sensing and catalytic domains of LigIIIα to other protein partners of the flexible XRCC1 scaffold.
History
DepositionApr 7, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 30, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 20, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: X-ray repair cross complementing protein 1 variant
B: X-ray repair cross complementing protein 1 variant


Theoretical massNumber of molelcules
Total (without water)22,8402
Polymers22,8402
Non-polymers00
Water95553
1
A: X-ray repair cross complementing protein 1 variant

B: X-ray repair cross complementing protein 1 variant


Theoretical massNumber of molelcules
Total (without water)22,8402
Polymers22,8402
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1/2,-y,z+1/21
Buried area1150 Å2
ΔGint-9 kcal/mol
Surface area11090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.975, 54.348, 101.256
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein X-ray repair cross complementing protein 1 variant / XRCC1


Mass: 11419.856 Da / Num. of mol.: 2 / Fragment: Second BRCT domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: Q59HH7, UniProt: P18887*PLUS
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 2.35 Å3/Da / Density % sol: 47.61 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 10-14% PEG 3350, 0.1M Bis-Tris pH 5.5 and 0.2M MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 12.3.1 / Wavelength: 1.12712 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Apr 2, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.12712 Å / Relative weight: 1
ReflectionResolution: 2.4→30.89 Å / Num. obs: 8682 / % possible obs: 98.2 % / Redundancy: 3.6 % / Rsym value: 0.049 / Net I/σ(I): 18.3
Reflection shellResolution: 2.4→2.44 Å / Num. unique obs: 294 / Rsym value: 0.26

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1CDZ

1cdz


Resolution: 2.414→30.88 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.8
RfactorNum. reflection% reflection
Rfree0.257 867 9.99 %
Rwork0.2242 --
obs0.2273 8682 99.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 98.44 Å2 / Biso mean: 48.3827 Å2 / Biso min: 24.99 Å2
Refinement stepCycle: final / Resolution: 2.414→30.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1612 0 0 53 1665
Biso mean---43.6 -
Num. residues----191
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0021664
X-RAY DIFFRACTIONf_angle_d0.4862255
X-RAY DIFFRACTIONf_dihedral_angle_d3.214980
X-RAY DIFFRACTIONf_chiral_restr0.042221
X-RAY DIFFRACTIONf_plane_restr0.005300
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.4143-2.56550.35681450.3132123397
2.5655-2.76350.39871370.29781279100
2.7635-3.04140.32141480.27371296100
3.0414-3.4810.28321450.251289100
3.481-4.38370.23671390.20491318100
4.3837-5.170.18621530.17591400100
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)
13.78741.1367-0.14423.2653-1.55935.33890.07110.12860.1328-0.1007-0.1153-0.0665-0.1730.12620.00140.33020.01740.02030.30530.01790.3362-4.7371-3.391626.3942
23.60710.85570.37432.2793-0.25995.86310.022-0.1585-0.1066-0.0276-0.0287-0.11720.3215-0.10840.00650.3181-0.0597-0.02830.3221-0.00560.3671-9.96464.5187-0.2502
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resseq 538:632)A538 - 632
2X-RAY DIFFRACTION2(chain B and resseq 538:633)B538 - 633

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