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- PDB-6vkk: Crystal Structure of human PARP-1 CAT domain bound to inhibitor r... -

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Basic information

Entry
Database: PDB / ID: 6vkk
TitleCrystal Structure of human PARP-1 CAT domain bound to inhibitor rucaparib
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
Rucaparib / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsSteffen, J.D. / 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
D: Poly [ADP-ribose] polymerase 1
C: Poly [ADP-ribose] polymerase 1
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)168,72420
Polymers166,2904
Non-polymers2,43416
Water3,045169
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,2766
Polymers41,5721
Non-polymers7045
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,0844
Polymers41,5721
Non-polymers5123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1845
Polymers41,5721
Non-polymers6124
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1805
Polymers41,5721
Non-polymers6084
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.267, 107.902, 142.845
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21D
12A
22C
13A
23B
14D
24C
15D
25B
16C
26B

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: 662 - 1011 / Label seq-ID: 23 - 372

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

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-RPB / Rucaparib


Mass: 323.364 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H18FN3O / Feature type: SUBJECT OF INVESTIGATION / Comment: anticancer, inhibitor*YM
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 169 / 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: 2.42 Å3/Da / Density % sol: 49.09 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 2M Ammonium Sulfate, 5% PEG 400, 100 mM Tris

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 12.3.1 / Wavelength: 1.1158 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Aug 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1158 Å / Relative weight: 1
ReflectionResolution: 2.1→47.92 Å / Num. obs: 94458 / % possible obs: 99.8 % / Redundancy: 11.7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.028 / Rrim(I) all: 0.094 / Net I/σ(I): 16.3 / Num. measured all: 1105071 / Scaling rejects: 81
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.1-2.1412.31.3365766646780.7780.3951.3942100
11.5-47.929.70.03463826580.9990.0110.0364597.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
REFMAC5.8.0257refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5ds3

5ds3


Resolution: 2.1→20 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.929 / SU B: 13.189 / SU ML: 0.169 / SU R Cruickshank DPI: 0.2562 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.256 / ESU R Free: 0.197
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2607 4674 5 %RANDOM
Rwork0.2391 ---
obs0.2402 89014 99.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 145.22 Å2 / Biso mean: 55.022 Å2 / Biso min: 29.15 Å2
Baniso -1Baniso -2Baniso -3
1--0.44 Å20 Å20 Å2
2--1.06 Å20 Å2
3----0.62 Å2
Refinement stepCycle: final / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10786 0 159 169 11114
Biso mean--51.9 46.32 -
Num. residues----1369
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.01311160
X-RAY DIFFRACTIONr_bond_other_d0.0010.01710590
X-RAY DIFFRACTIONr_angle_refined_deg1.2371.63815072
X-RAY DIFFRACTIONr_angle_other_deg1.1231.5924702
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2351363
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.72523.806515
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.429152061
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.7211544
X-RAY DIFFRACTIONr_chiral_restr0.0510.21441
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212557
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022095
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A105270.08
12D105270.08
21A103910.09
22C103910.09
31A105710.08
32B105710.08
41D104630.09
42C104630.09
51D104650.09
52B104650.09
61C105930.08
62B105930.08
LS refinement shellResolution: 2.1→2.154 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.31 301 -
Rwork0.293 6550 -
all-6851 -
obs--100 %
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)
12.9038-0.31630.29232.4703-0.51261.9040.0456-0.25640.15710.1202-0.0592-0.15550.02730.19780.01370.1171-0.0143-0.00910.0622-0.00340.0233-4.26017.533912.238
23.68730.35622.56844.9706-1.68064.6310.09530.173-0.4861-0.23630.15150.30.6069-0.158-0.24690.4071-0.0433-0.05060.0646-0.00590.1694-22.0238-10.6924.5221
31.47760.22490.28531.6752-0.20843.43430.03680.0689-0.16770.03810.0748-0.14230.33770.0361-0.11170.19570.011-0.08410.0062-0.01530.0589-25.694117.6733-24.6565
45.5261-2.2947-0.55583.47371.10833.81790.06340.4460.0051-0.2697-0.07820.1719-0.1969-0.43970.01470.2864-0.0121-0.02520.13850.02990.0188-39.917630.337-43.1516
52.5915-0.0297-0.09953.64180.04612.27960.1391-0.47150.20970.2057-0.0306-0.099-0.2190.0973-0.10850.197-0.07630.03290.162-0.08070.0597-22.472953.29837.83
66.7624-0.4599-2.28594.26790.75092.73270.19930.43170.8936-0.27960.0409-0.4773-0.58760.2401-0.24020.5329-0.11640.1490.2241-0.04040.4011-8.614769.6126-7.1384
75.48552.0189-0.05233.47590.00972.66850.07340.1193-0.48970.3607-0.07910.23550.45210.17250.00570.22270.07680.07380.11880.05020.1761-43.548516.379919.9591
85.50482.5799-0.11675.3806-1.49522.67420.5916-1.21430.00161.2784-0.6241-0.2918-0.00840.52230.03250.7352-0.0851-0.06950.71480.09290.177-27.29526.058237.7856
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A664 - 689
2X-RAY DIFFRACTION1A790 - 1011
3X-RAY DIFFRACTION2A690 - 780
4X-RAY DIFFRACTION3B664 - 689
5X-RAY DIFFRACTION3B790 - 1011
6X-RAY DIFFRACTION4B690 - 780
7X-RAY DIFFRACTION5C664 - 689
8X-RAY DIFFRACTION5C790 - 1011
9X-RAY DIFFRACTION6C690 - 780
10X-RAY DIFFRACTION7D664 - 689
11X-RAY DIFFRACTION7D790 - 1011
12X-RAY DIFFRACTION8D690 - 780

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