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

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Basic information

Entry
Database: PDB / ID: 7aab
TitleCrystal structure of the catalytic domain of human PARP1 in complex with inhibitor EB-47
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE / PARP inhibitor / PARylation / substrate mimetic / inhibitor / NADH analog / EB47
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 / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of base-excision repair / 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 / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of base-excision repair / 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 / negative regulation of adipose tissue development / NAD DNA ADP-ribosyltransferase activity / DNA ADP-ribosylation / mitochondrial DNA metabolic process / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / replication fork reversal / ATP generation from poly-ADP-D-ribose / positive regulation of necroptotic process / transcription regulator activator activity / response to aldosterone / HDR through MMEJ (alt-NHEJ) / positive regulation of DNA-templated transcription, elongation / NAD+ ADP-ribosyltransferase / signal transduction involved in regulation of gene expression / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / mitochondrial DNA repair / NAD+-protein-aspartate ADP-ribosyltransferase activity / protein poly-ADP-ribosylation / positive regulation of intracellular estrogen receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / positive regulation of cardiac muscle hypertrophy / NAD+-protein-glutamate ADP-ribosyltransferase activity / positive regulation of mitochondrial depolarization / cellular response to zinc ion / NAD+-protein mono-ADP-ribosyltransferase activity / nuclear replication fork / decidualization / protein autoprocessing / R-SMAD binding / site of DNA damage / negative regulation of transcription elongation by RNA polymerase II / macrophage differentiation / Transferases; Glycosyltransferases; Pentosyltransferases / NAD+ poly-ADP-ribosyltransferase activity / positive regulation of SMAD protein signal transduction / POLB-Dependent Long Patch Base Excision Repair / SUMOylation of DNA damage response and repair proteins / positive regulation of double-strand break repair via homologous recombination / nucleosome binding / protein localization to chromatin / nucleotidyltransferase activity / telomere maintenance / transforming growth factor beta receptor signaling pathway / negative regulation of innate immune response / nuclear estrogen receptor binding / response to gamma radiation / mitochondrion organization / enzyme activator activity / Downregulation of SMAD2/3:SMAD4 transcriptional activity / protein-DNA complex / cellular response to nerve growth factor stimulus / DNA Damage Recognition in GG-NER / protein modification process / Dual Incision in GG-NER / positive regulation of protein localization to nucleus / Formation of Incision Complex in GG-NER / histone deacetylase binding / cellular response to insulin stimulus / NAD binding / cellular response to amyloid-beta / cellular response to UV / nuclear envelope / double-strand break repair / regulation of protein localization / site of double-strand break / cellular response to oxidative stress / transcription regulator complex / damaged DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription by RNA polymerase II / chromosome, telomeric region / positive regulation of canonical NF-kappaB signal transduction / nuclear body / innate immune response / DNA repair / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / DNA damage response / chromatin binding / protein kinase binding / chromatin / nucleolus / enzyme binding / negative regulation of transcription by RNA polymerase II / 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-UHB / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.8 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
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)80,0858
Polymers78,6262
Non-polymers1,4596
Water37821
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0434
Polymers39,3131
Non-polymers7303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0434
Polymers39,3131
Non-polymers7303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)134.899, 134.899, 111.388
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61

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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 BL21(DE3) (bacteria) / Variant (production host): Gold
References: UniProt: P09874, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical ChemComp-UHB / 2-[4-[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]carbonylpiperazin-1-yl]-N-(1-oxidanylidene-2,3-dihydroisoindol-4-yl)ethanamide


Mass: 537.528 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C24H27N9O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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

Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5.5
Details: 0.4 M ammonium sulfate, 25 % PEG3350, 0.1 M PCTP pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97623 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 29, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97623 Å / Relative weight: 1
ReflectionResolution: 1.43→116.83 Å / Num. obs: 130609 / % possible obs: 61.3 % / Redundancy: 7.7 % / Biso Wilson estimate: 75.44 Å2 / CC1/2: 0.055 / Rmerge(I) obs: 2.499 / Rpim(I) all: 1.077 / Rrim(I) all: 2.754 / Net I/σ(I): 1.3 / Num. measured all: 1009989 / Scaling rejects: 1937
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Num. unique obsRpim(I) allRrim(I) all% possible allRmerge(I) obsCC1/2
1.43-1.51.4463732.44646.18115
4.51-116.8310.168910.0420.1321000.1260.996

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Phasing

PhasingMethod: molecular replacement

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Processing

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

Resolution: 2.8→116.83 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.881 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.359
RfactorNum. reflection% reflectionSelection details
Rfree0.224 962 4.9 %RANDOM
Rwork0.202 ---
obs0.203 19625 69.3 %-
Displacement parametersBiso max: 149.22 Å2 / Biso mean: 66.52 Å2 / Biso min: 4.16 Å2
Baniso -1Baniso -2Baniso -3
1--3.7361 Å20 Å20 Å2
2---3.7361 Å20 Å2
3---7.4721 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: final / Resolution: 2.8→116.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5388 0 98 21 5507
Biso mean--58.01 26.16 -
Num. residues----700
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1955SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes989HARMONIC5
X-RAY DIFFRACTIONt_it5597HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion740SEMIHARMONIC5
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_contact5928SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5597HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg7595HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.1
X-RAY DIFFRACTIONt_other_torsion19.99
LS refinement shellResolution: 2.8→2.95 Å / Rfactor Rfree error: 0 / Total num. of bins used: 48
RfactorNum. reflection% reflection
Rfree0.2574 20 4.89 %
Rwork0.262 389 -
all0.2618 409 -
obs--10.26 %
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)
13.9490.6597-0.69952.1315-0.63370.91940.03020.27170.2698-0.11170.07050.3056-0.0399-0.119-0.1008-0.161-0.0282-0.0846-0.15970.0516-0.0884-35.291227.2822-13.3905
23.05230.982-0.58833.0437-0.11350.86030.0972-0.1380.32750.23590.0037-0.0326-0.0804-0.0017-0.101-0.19-0.0134-0.0098-0.1174-0.1003-0.1519-3.068344.563413.427
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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