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- PDB-6vko: Crystal Structure of human PARP-1 CAT domain bound to inhibitor UKTT15 -

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Basic information

Entry
Database: PDB / ID: 6vko
TitleCrystal Structure of human PARP-1 CAT domain bound to inhibitor UKTT15
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE/INHIBITOR / PARP-1 / poly(ADP-ribose) polymerase / PARP inhibitor / PARP1 / ARTD1 / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / regulation of base-excision repair / positive regulation of myofibroblast differentiation / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / carbohydrate biosynthetic process / positive regulation of single strand break repair ...NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / regulation of base-excision repair / positive regulation of myofibroblast differentiation / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / carbohydrate biosynthetic process / positive regulation of single strand break repair / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis / negative regulation of adipose tissue development / NAD+-protein-serine ADP-ribosyltransferase activity / NAD DNA ADP-ribosyltransferase activity / NAD+-protein-aspartate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / mitochondrial DNA metabolic process / DNA ADP-ribosylation / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / signal transduction involved in regulation of gene expression / positive regulation of necroptotic process / regulation of catalytic activity / ATP generation from poly-ADP-D-ribose / replication fork reversal / transcription regulator activator activity / HDR through MMEJ (alt-NHEJ) / positive regulation of DNA-templated transcription, elongation / positive regulation of intracellular estrogen receptor signaling pathway / NAD+ ADP-ribosyltransferase / cellular response to zinc ion / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / positive regulation of mitochondrial depolarization / response to aldosterone / mitochondrial DNA repair / negative regulation of cGAS/STING signaling pathway / protein poly-ADP-ribosylation / positive regulation of cardiac muscle hypertrophy / negative regulation of transcription elongation by RNA polymerase II / nuclear replication fork / NAD+-protein ADP-ribosyltransferase activity / site of DNA damage / R-SMAD binding / positive regulation of SMAD protein signal transduction / macrophage differentiation / protein autoprocessing / decidualization / Transferases; Glycosyltransferases; Pentosyltransferases / positive regulation of double-strand break repair via homologous recombination / NAD+-protein poly-ADP-ribosyltransferase activity / POLB-Dependent Long Patch Base Excision Repair / SUMOylation of DNA damage response and repair proteins / nucleosome binding / protein localization to chromatin / negative regulation of innate immune response / telomere maintenance / nucleotidyltransferase activity / mitochondrion organization / transforming growth factor beta receptor signaling pathway / cellular response to nerve growth factor stimulus / nuclear estrogen receptor binding / response to gamma radiation / protein-DNA complex / Downregulation of SMAD2/3:SMAD4 transcriptional activity / DNA Damage Recognition in GG-NER / protein modification process / Dual Incision in GG-NER / Formation of Incision Complex in GG-NER / histone deacetylase binding / positive regulation of protein localization to nucleus / cellular response to amyloid-beta / cellular response to insulin stimulus / regulation of protein localization / cellular response to UV / NAD binding / double-strand break repair / nuclear envelope / site of double-strand break / cellular response to oxidative stress / positive regulation of canonical NF-kappaB signal transduction / RNA polymerase II-specific DNA-binding transcription factor binding / transcription regulator complex / transcription by RNA polymerase II / chromosome, telomeric region / damaged DNA binding / nuclear body / DNA repair / innate immune response / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / DNA damage response / chromatin binding / chromatin / nucleolus / protein kinase binding / enzyme binding / negative regulation of transcription by RNA polymerase II / protein homodimerization activity
Similarity search - Function
: / PADR1, N-terminal helical domain / PADR1 domain profile. / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / PADR1 domain, zinc ribbon fold / PADR1 / Zinc finger poly(ADP-ribose) polymerase (PARP)-type signature. / Zinc finger, PARP-type superfamily ...: / PADR1, N-terminal helical domain / PADR1 domain profile. / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / PADR1 domain, zinc ribbon fold / PADR1 / 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 / Zinc finger, PARP-type / WGR domain profile. / Poly(ADP-ribose) polymerase, regulatory domain / WGR domain / WGR domain superfamily / WGR domain / Proposed nucleic acid binding domain / Poly(ADP-ribose) polymerase, regulatory domain superfamily / Poly(ADP-ribose) polymerase, regulatory domain / PARP alpha-helical domain profile. / Phosphoenolpyruvate Carboxykinase; domain 3 - #10 / Phosphoenolpyruvate Carboxykinase; domain 3 / BRCA1 C Terminus (BRCT) domain / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / breast cancer carboxy-terminal domain / BRCT domain profile. / BRCT domain / BRCT domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-L1S / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsLangelier, M.F. / Pascal, J.M.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)BMA342854 Canada
CitationJournal: Science / Year: 2020
Title: Structural basis for allosteric PARP-1 retention on DNA breaks.
Authors: Zandarashvili, L. / Langelier, M.F. / Velagapudi, U.K. / Hancock, M.A. / Steffen, J.D. / Billur, R. / Hannan, Z.M. / Wicks, A.J. / Krastev, D.B. / Pettitt, S.J. / Lord, C.J. / Talele, T.T. / ...Authors: Zandarashvili, L. / Langelier, M.F. / Velagapudi, U.K. / Hancock, M.A. / Steffen, J.D. / Billur, R. / Hannan, Z.M. / Wicks, A.J. / Krastev, D.B. / Pettitt, S.J. / Lord, C.J. / Talele, T.T. / Pascal, J.M. / Black, B.E.
History
DepositionJan 21, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_radiation_wavelength.wavelength / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Poly [ADP-ribose] polymerase 1
B: Poly [ADP-ribose] polymerase 1
C: Poly [ADP-ribose] polymerase 1
D: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,38520
Polymers166,2904
Non-polymers3,09516
Water55831
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3465
Polymers41,5721
Non-polymers7744
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3465
Polymers41,5721
Non-polymers7744
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3465
Polymers41,5721
Non-polymers7744
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3465
Polymers41,5721
Non-polymers7744
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)139.701, 129.751, 102.720
Angle α, β, γ (deg.)90.000, 111.360, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / End auth comp-ID: THR / End label comp-ID: THR / Refine code: _ / Auth seq-ID: 664 - 1011 / Label seq-ID: 25 - 372

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
Poly [ADP-ribose] polymerase 1 / PARP-1 / ADP-ribosyltransferase diphtheria toxin-like 1 / ARTD1 / DNA ADP-ribosyltransferase PARP1 ...PARP-1 / ADP-ribosyltransferase diphtheria toxin-like 1 / ARTD1 / DNA ADP-ribosyltransferase PARP1 / NAD(+) ADP-ribosyltransferase 1 / ADPRT 1 / Poly[ADP-ribose] synthase 1 / Protein poly-ADP-ribosyltransferase PARP1


Mass: 41572.461 Da / Num. of mol.: 4 / Fragment: catalytic domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL / Production host: Escherichia coli (E. coli)
References: UniProt: P09874, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical
ChemComp-L1S / methyl 2-{4-[4-(7-carbamoyl-1H-benzimidazol-2-yl)benzene-1-carbonyl]piperazin-1-yl}pyrimidine-5-carboxylate


Mass: 485.495 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H23N7O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.61 Å3/Da / Density % sol: 52.82 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 2M Ammonium Sulfate, Bis-Tris pH6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.1158 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1158 Å / Relative weight: 1
ReflectionResolution: 2.8→95.664 Å / Num. all: 39944 / Num. obs: 39944 / % possible obs: 95.4 % / Redundancy: 4.6 % / Rpim(I) all: 0.076 / Rrim(I) all: 0.17 / Rsym value: 0.152 / Net I/av σ(I): 2.6 / Net I/σ(I): 5.3 / Num. measured all: 184578
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.8-2.954.50.7091.12610158000.3590.7990.7091.895.5
2.95-3.134.20.4431.72341755230.2330.5040.4432.595.6
3.13-3.354.30.2752.72219351210.1430.3120.2753.894.7
3.35-3.614.80.2611.22345548780.1320.2940.2615.196.5
3.61-3.964.30.2151.51910244060.1140.2450.2155.994.2
3.96-4.435.10.12852038639760.060.1420.1287.795.1
4.43-5.114.90.1025.91753435930.050.1140.1028.396.5
5.11-6.2650.1016.31502630240.0490.1130.1017.895.7
6.26-8.854.70.0787.41084123250.0380.0870.078895.5
8.85-47.83250.0657.8652312980.0290.0710.065994.5

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALA3.3.22data scaling
REFMAC5.8.0257refinement
PDB_EXTRACT3.25data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5ds3

5ds3


Resolution: 2.8→20 Å / Cor.coef. Fo:Fc: 0.856 / Cor.coef. Fo:Fc free: 0.834 / SU B: 47.323 / SU ML: 0.454 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.488
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.3122 2021 5.1 %RANDOM
Rwork0.2843 ---
obs0.2857 37777 94.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 214.52 Å2 / Biso mean: 90.658 Å2 / Biso min: 41.27 Å2
Baniso -1Baniso -2Baniso -3
1-1.51 Å20 Å22.05 Å2
2---2.25 Å20 Å2
3----0.67 Å2
Refinement stepCycle: final / Resolution: 2.8→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10712 0 204 31 10947
Biso mean--89.2 56.66 -
Num. residues----1360
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01311147
X-RAY DIFFRACTIONr_bond_other_d0.0010.01710517
X-RAY DIFFRACTIONr_angle_refined_deg1.4711.63615068
X-RAY DIFFRACTIONr_angle_other_deg1.0911.59124518
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.74651360
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.4423.798516
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.359152044
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8761544
X-RAY DIFFRACTIONr_chiral_restr0.0570.21428
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212735
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022109
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A108520.02
12B108520.02
21A108270.02
22C108270.02
31A108230.03
32D108230.03
41B108320.02
42C108320.02
51B108190.02
52D108190.02
61C108320.02
62D108320.02
LS refinement shellResolution: 2.8→2.871 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.33 160 -
Rwork0.325 2709 -
all-2869 -
obs--95.19 %
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)
14.7044-0.6597-1.23044.61810.16923.9935-0.1180.1772-0.667-0.3691-0.14530.40380.6005-0.72270.26330.1962-0.09680.01740.3903-0.06770.121727.3682-24.115776.4313
20.687-1.4127-0.33136.35460.98840.2373-0.29370.0123-0.7635-0.87760.16090.37940.07960.22890.13271.1333-0.02550.45711.1649-0.2491.396642.6371-43.757965.7784
33.7315-0.0261-0.04393.8241.38114.7147-0.03580.41090.3815-0.1431-0.11070.4898-0.6648-0.43760.14640.16080.0676-0.03010.4040.03560.10498.16539.737996.5495
44.9566-1.10970.76812.62182.83733.98630.04830.72070.3598-0.2934-0.70680.4605-0.1111-0.51550.65851.020.249-0.28061.5764-0.21980.6396-4.5363-0.659274.9942
53.3164-0.17660.47933.9670.03044.9064-0.0704-0.13810.40880.0414-0.0273-0.5299-0.49820.54970.09770.0838-0.1314-0.02050.26640.00080.116730.616920.3248132.8307
62.0241-0.86372.41836.6947-1.10833.1212-0.6140.2140.3966-1.12440.2546-0.6731-0.8684-0.18840.35941.2248-0.2744-0.06131.12820.26840.609926.856839.9978114.556
74.49020.3564-0.09444.2656-1.0394.0705-0.1401-0.0897-0.61160.18030.0041-0.45940.51270.42380.1360.11520.13440.00650.27650.02230.123630.9625-13.7964160.4637
85.9743.05220.65294.5142-1.13810.84440.23631.123-0.1144-0.0252-0.4466-0.7480.00010.71270.21030.54070.22590.19611.40570.16020.984754.9974-3.6251153.0334
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A664 - 689
2X-RAY DIFFRACTION1A790 - 1011
3X-RAY DIFFRACTION2A690 - 781
4X-RAY DIFFRACTION3B664 - 689
5X-RAY DIFFRACTION3B790 - 1011
6X-RAY DIFFRACTION4B690 - 781
7X-RAY DIFFRACTION5C664 - 689
8X-RAY DIFFRACTION5C790 - 1011
9X-RAY DIFFRACTION6C690 - 781
10X-RAY DIFFRACTION7D664 - 689
11X-RAY DIFFRACTION7D790 - 1011
12X-RAY DIFFRACTION8D690 - 781

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