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- PDB-6wh1: Structure of the complex of human DNA ligase III-alpha and XRCC1 ... -

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Basic information

Entry
Database: PDB / ID: 6wh1
TitleStructure of the complex of human DNA ligase III-alpha and XRCC1 BRCT domains
Components
  • DNA ligase 3 alpha
  • X-ray repair cross complementing protein 1 variant
KeywordsDNA BINDING PROTEIN/LIGASE / DNA ligase complex / DNA repair / DNA BINDING PROTEIN / DNA BINDING PROTEIN-LIGASE complex
Function / homology
Function and homology information


DNA ligase III-XRCC1 complex / negative regulation of mitochondrial DNA replication / 3' overhang single-stranded DNA endodeoxyribonuclease activity / oxidized DNA binding / positive regulation of DNA ligase activity / 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 ...DNA ligase III-XRCC1 complex / negative regulation of mitochondrial DNA replication / 3' overhang single-stranded DNA endodeoxyribonuclease activity / oxidized DNA binding / positive regulation of DNA ligase activity / 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 / base-excision repair, DNA ligation / DNA ligase activity / poly-ADP-D-ribose binding / DNA ligase (ATP) / positive regulation of single strand break repair / DNA ligase (ATP) activity / voluntary musculoskeletal movement / cerebellum morphogenesis / single strand break repair / replication-born double-strand break repair via sister chromatid exchange / DNA ligation / HDR through MMEJ (alt-NHEJ) / lagging strand elongation / response to hydroperoxide / mitochondrial DNA repair / Resolution of AP sites via the single-nucleotide replacement pathway / DNA biosynthetic process / double-strand break repair via alternative nonhomologous end joining / APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway / site of DNA damage / mitochondrion organization / Gap-filling DNA repair synthesis and ligation in GG-NER / base-excision repair, gap-filling / : / hippocampus development / double-strand break repair via homologous recombination / base-excision repair / double-strand break repair via nonhomologous end joining / Gap-filling DNA repair synthesis and ligation in TC-NER / double-strand break repair / chromosome, telomeric region / damaged DNA binding / response to hypoxia / response to xenobiotic stimulus / cell cycle / cell division / chromatin / nucleolus / enzyme binding / mitochondrion / DNA binding / zinc ion binding / nucleoplasm / ATP binding / nucleus
Similarity search - Function
DNA ligase 3, BRCT domain / DNA ligase 3 BRCT domain / DNA-repair protein Xrcc1, N-terminal / XRCC1, first (central) BRCT domain / XRCC1 N terminal domain / DNA ligase, ATP-dependent / DNA ligase, ATP-dependent, N-terminal / DNA ligase, ATP-dependent, N-terminal domain superfamily / DNA ligase N terminus / ATP-dependent DNA ligase signature 2. ...DNA ligase 3, BRCT domain / DNA ligase 3 BRCT domain / DNA-repair protein Xrcc1, N-terminal / XRCC1, first (central) BRCT domain / XRCC1 N terminal domain / DNA ligase, ATP-dependent / DNA ligase, ATP-dependent, N-terminal / DNA ligase, ATP-dependent, N-terminal domain superfamily / DNA ligase N terminus / ATP-dependent DNA ligase signature 2. / ATP-dependent DNA ligase AMP-binding site. / DNA ligase, ATP-dependent, C-terminal / ATP dependent DNA ligase C terminal region / DNA ligase, ATP-dependent, conserved site / ATP-dependent DNA ligase family profile. / Zinc finger poly(ADP-ribose) polymerase (PARP)-type signature. / Zinc finger, PARP-type superfamily / Poly(ADP-ribose) polymerase and DNA-Ligase Zn-finger region / Zinc finger poly(ADP-ribose) polymerase (PARP)-type profile. / Poly(ADP-ribose) polymerase and DNA-Ligase Zn-finger region / DNA ligase, ATP-dependent, central / ATP dependent DNA ligase domain / Zinc finger, PARP-type / BRCT domain, a BRCA1 C-terminus domain / BRCA1 C Terminus (BRCT) domain / breast cancer carboxy-terminal domain / BRCT domain profile. / BRCT domain / BRCT domain superfamily / Galactose-binding-like domain superfamily / Nucleic acid-binding, OB-fold
Similarity search - Domain/homology
DNA repair protein XRCC1 / DNA ligase 3 / X-ray repair cross complementing protein 1 variant
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MAD / Resolution: 2.4 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 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: DNA ligase 3 alpha


Theoretical massNumber of molelcules
Total (without water)20,3832
Polymers20,3832
Non-polymers00
Water32418
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.073, 88.073, 43.039
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z

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Components

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


Mass: 11419.856 Da / Num. of mol.: 1 / Fragment: C-terminal 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: Protein DNA ligase 3 alpha / DNA ligase III alpha / Polydeoxyribonucleotide synthase [ATP] 3 alpha


Mass: 8963.312 Da / Num. of mol.: 1 / Fragment: BRCT domain / Mutation: C922S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LIG3 / Production host: Escherichia coli (E. coli) / References: UniProt: P49916, DNA ligase (ATP)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 2.36 Å3/Da / Density % sol: 47.97 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 8-10% isopropanol and 0.1M Bis-Tris pH 5.5

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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 9, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.12712 Å / Relative weight: 1
ReflectionResolution: 2.4→37.483 Å / Num. obs: 6860 / % possible obs: 98.4 % / Redundancy: 5 % / Rsym value: 0.041 / Net I/σ(I): 29.9
Reflection shellResolution: 2.4→2.46 Å / Num. unique obs: 376 / Rsym value: 0.477 / % possible all: 97.8

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Processing

Software
NameVersionClassification
PHENIX1.17.1refinement
HKL-2000data reduction
HKL-2000data scaling
SOLVEphasing
RefinementMethod to determine structure: MAD / Resolution: 2.4→37.48 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.916 / SU B: 23.399 / SU ML: 0.249 / Cross valid method: FREE R-VALUE / ESU R: 0.597 / ESU R Free: 0.308
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.272 741 9.7 %RANDOM
Rwork0.221 ---
obs0.226 6860 98.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 147.72 Å2 / Biso mean: 67.21 Å2 / Biso min: 25.08 Å2
Baniso -1Baniso -2Baniso -3
1-0.5 Å20.25 Å20 Å2
2--0.5 Å20 Å2
3----0.76 Å2
Refinement stepCycle: final / Resolution: 2.4→37.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1374 0 0 37 1411
Biso mean---64.31 -
Num. residues----172
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00531417
X-RAY DIFFRACTIONf_angle_d0.69341932
X-RAY DIFFRACTIONf_chiral_restr0.0459205
X-RAY DIFFRACTIONf_plane_restr0.0046252
X-RAY DIFFRACTIONf_dihedral_angle_d6.8607830
LS refinement shellResolution: 2.4→2.46 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.406 51 -
Rwork0.284 493 -
all-544 -
obs--97.84 %
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)
16.5578-1.33842.04133.1687-0.29095.81590.10650.1693-0.16130.0428-0.0038-0.00040.34660.2311-0.10270.05160.0171-0.00860.06390.02130.019663.139492.90638.9324
29.09350.95021.03366.0728-0.99097.46460.5489-0.7527-0.69590.97250.1181-0.04620.21330.7994-0.6670.26570.1444-0.130.3697-0.10440.22583.661688.96722.6821
30.4851-0.05140.23230.99680.75950.73590.0077-0.0757-0.05610.1053-0.07820.12210.0558-0.11120.07050.22080.0395-0.00240.18040.03430.214760.149689.841416.8171
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A538 - 632
2X-RAY DIFFRACTION2B845 - 921
3X-RAY DIFFRACTION3A1 - 54
4X-RAY DIFFRACTION3B19 - 38

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