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- PDB-7aad: Crystal structure of the catalytic domain of human PARP1 in compl... -

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Basic information

Entry
Database: PDB / ID: 7aad
TitleCrystal structure of the catalytic domain of human PARP1 in complex with olaparib
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE / PARP inhibitor / synthetic lethal / inhibitor
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 / positive regulation of myofibroblast differentiation / regulation of base-excision repair / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / positive regulation of single strand break repair / regulation of circadian sleep/wake cycle, non-REM sleep ...NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / positive regulation of myofibroblast differentiation / regulation of base-excision repair / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / positive regulation of single strand break repair / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis / carbohydrate biosynthetic process / NAD+-protein-serine ADP-ribosyltransferase activity / regulation of catalytic activity / negative regulation of adipose tissue development / NAD DNA ADP-ribosyltransferase activity / NAD+-protein-aspartate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / DNA ADP-ribosylation / mitochondrial DNA metabolic process / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / replication fork reversal / signal transduction involved in regulation of gene expression / positive regulation of necroptotic process / ATP generation from poly-ADP-D-ribose / transcription regulator activator activity / HDR through MMEJ (alt-NHEJ) / negative regulation of cGAS/STING signaling pathway / 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 / mitochondrial DNA repair / response to aldosterone / protein poly-ADP-ribosylation / positive regulation of mitochondrial depolarization / positive regulation of cardiac muscle hypertrophy / nuclear replication fork / negative regulation of transcription elongation by RNA polymerase II / NAD+-protein ADP-ribosyltransferase activity / site of DNA damage / R-SMAD binding / positive regulation of SMAD protein signal transduction / protein autoprocessing / macrophage differentiation / decidualization / NAD+-protein poly-ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / nucleosome binding / POLB-Dependent Long Patch Base Excision Repair / positive regulation of double-strand break repair via homologous recombination / SUMOylation of DNA damage response and repair proteins / negative regulation of innate immune response / protein localization to chromatin / telomere maintenance / nucleotidyltransferase activity / transforming growth factor beta receptor signaling pathway / cellular response to nerve growth factor stimulus / protein-DNA complex / response to gamma radiation / mitochondrion organization / nuclear estrogen receptor binding / Downregulation of SMAD2/3:SMAD4 transcriptional activity / DNA Damage Recognition in GG-NER / protein modification process / Dual Incision in GG-NER / histone deacetylase binding / cellular response to insulin stimulus / Formation of Incision Complex in GG-NER / positive regulation of protein localization to nucleus / cellular response to amyloid-beta / cellular response to UV / NAD binding / double-strand break repair / nuclear envelope / regulation of protein localization / 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 / damaged DNA binding / chromosome, telomeric region / nuclear body / innate immune response / DNA repair / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / ubiquitin protein ligase binding / chromatin / nucleolus / apoptotic process / protein kinase binding / negative regulation of transcription by RNA polymerase II / enzyme binding / protein homodimerization activity
Similarity search - Function
Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / : / PADR1 domain, zinc ribbon fold / PADR1, N-terminal helical domain / PADR1 domain profile. / PADR1 / Zinc finger poly(ADP-ribose) polymerase (PARP)-type signature. / Zinc finger, PARP-type superfamily ...Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / : / PADR1 domain, zinc ribbon fold / PADR1, N-terminal helical domain / PADR1 domain profile. / 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 / : / Poly(ADP-ribose) polymerase, regulatory domain / WGR domain / WGR domain superfamily / WGR domain / WGR domain profile. / Proposed nucleic acid binding domain / Poly(ADP-ribose) polymerase, regulatory domain superfamily / Poly(ADP-ribose) polymerase, regulatory domain / PARP alpha-helical domain profile. / 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
Similarity search - Domain/homology
Chem-09L / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.21 Å
AuthorsSchimpl, M. / Ogden, T.E.H. / Yang, J.-C. / Easton, L.E. / Underwood, E. / Rawlins, P.B. / Johannes, J.W. / Embrey, K.J. / Neuhaus, D.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)U105178934 United Kingdom
CitationJournal: Nucleic Acids Res. / Year: 2021
Title: Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition.
Authors: Ogden, T.E.H. / Yang, J.C. / Schimpl, M. / Easton, L.E. / Underwood, E. / Rawlins, P.B. / McCauley, M.M. / Langelier, M.F. / Pascal, J.M. / Embrey, K.J. / Neuhaus, D.
History
DepositionSep 4, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 10, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 10, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3May 1, 2024Group: 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)79,7837
Polymers78,6262
Non-polymers1,1575
Water1,892105
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9404
Polymers39,3131
Non-polymers6273
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8433
Polymers39,3131
Non-polymers5312
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.981, 91.555, 162.133
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 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: 39312.934 Da / Num. of mol.: 2 / Fragment: catalytic domain (662-1101)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL / Plasmid: pET24a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 Gold (DE3)
References: UniProt: P09874, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical ChemComp-09L / 4-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)phthalazin-1(2H)-one / Olaparib


Mass: 434.463 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C24H23FN4O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / 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: 2.26 Å3/Da / Density % sol: 45.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5 / Details: 2.5 M ammonium sulfate, 0.1 M Tris pH 8.5

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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 EIGER X 16M / Detector: PIXEL / Date: Feb 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.21→81.07 Å / Num. obs: 26338 / % possible obs: 89.8 % / Redundancy: 9.9 % / Biso Wilson estimate: 34.65 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.185 / Rpim(I) all: 0.061 / Rrim(I) all: 0.195 / Net I/σ(I): 9.1
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
2.212-2.3329.61.3631258713180.8090.4571.4391.579
6.942-81.0669.50.0571256213170.9990.0190.0626.199.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
AMoREphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 2.21→81.07 Å / Cor.coef. Fo:Fc: 0.91 / Cor.coef. Fo:Fc free: 0.884 / SU R Cruickshank DPI: 0.672 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.687 / SU Rfree Blow DPI: 0.286 / SU Rfree Cruickshank DPI: 0.289
RfactorNum. reflection% reflectionSelection details
Rfree0.254 1324 5.03 %RANDOM
Rwork0.223 ---
obs0.225 26338 71.9 %-
Displacement parametersBiso max: 140.12 Å2 / Biso mean: 39.33 Å2 / Biso min: 12.21 Å2
Baniso -1Baniso -2Baniso -3
1--1.2025 Å20 Å20 Å2
2--5.2331 Å20 Å2
3----4.0305 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.21→81.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5460 0 79 105 5644
Biso mean--31.84 25.96 -
Num. residues----700
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1998SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes940HARMONIC5
X-RAY DIFFRACTIONt_it5648HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion732SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6388SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5648HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg7640HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion2.41
X-RAY DIFFRACTIONt_other_torsion17.94
LS refinement shellResolution: 2.21→2.27 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2358 22 4.17 %
Rwork0.2274 505 -
all0.2278 527 -
obs--18.94 %
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)
11.26210.2319-0.05391.1846-0.1241.7533-0.0063-0.009-0.01580.0246-0.0431-0.02930.0114-0.11720.0493-0.13040.0431-0.0092-0.0185-0.0157-0.157410.101843.20884.6518
20.77480.05030.18430.8624-0.58576.0718-0.03890.0011-0.0761-0.0380.06320.00430.2369-0.2177-0.0243-0.1256-0.0309-0.013-0.0036-0.0015-0.086730.477126.798837.9449
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A662 - 1011
2X-RAY DIFFRACTION2{ B|* }B662 - 1011

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