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- PDB-6xvw: Catalytic domain of human PARP-1 in complex with the inhibitor MC2050 -

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Basic information

Entry
Database: PDB / ID: 6xvw
TitleCatalytic domain of human PARP-1 in complex with the inhibitor MC2050
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE / Inhibitor / Complex / DNA-repair
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
NICKEL (II) ION / Chem-O3H / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsPfahler, J. / Steegborn, C.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: From PARP1 to TNKS2 Inhibition: A Structure-Based Approach.
Authors: Tomassi, S. / Pfahler, J. / Mautone, N. / Rovere, A. / Esposito, C. / Passeri, D. / Pellicciari, R. / Novellino, E. / Pannek, M. / Steegborn, C. / Paiardini, A. / Mai, A. / Rotili, D.
History
DepositionJan 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 3, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,03118
Polymers79,4472
Non-polymers1,58416
Water6,341352
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,69812
Polymers39,7231
Non-polymers97511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3326
Polymers39,7231
Non-polymers6095
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)68.172, 86.727, 127.635
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab

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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: 39723.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL
Details (production host): Senp2-cleavable N-terminal His6-SUMO tag
Production host: Escherichia coli (E. coli)
References: UniProt: P09874, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical
ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ni
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-O3H / 2-[2-(4-pyridin-2-ylpiperazin-1-yl)ethylsulfanyl]-3~{H}-quinazolin-4-one


Mass: 367.468 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H21N5OS / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 352 / 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: 2.37 Å3/Da / Density % sol: 48.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1 M TRIS pH 8.5, 20% (w/w) PEG 2.000 MME, 0.01 M NiCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1.00002 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Feb 14, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 2→71.734 Å / Num. obs: 96367 / % possible obs: 97.6 % / Redundancy: 2.334 % / Biso Wilson estimate: 49.047 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.072 / Rrim(I) all: 0.092 / Net I/σ(I): 7.62
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
2-2.122.2871.4740.6151740.2131.88495.9
2.12-2.272.3190.9121.03151370.4141.1798.4
2.27-2.452.2520.5521.73135480.6810.71698
2.45-2.682.3880.3053.19124150.880.39298
2.68-32.4390.1655.73115710.9660.21198.3
3-3.462.2820.07411.199890.9930.09698
3.46-4.232.3680.03521.1184080.9980.04597.3
4.23-5.982.3940.02627.5965400.9990.03497
5.98-71.7342.3470.02131.0435850.9990.02796.9

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XSCALEdata scaling
XDSdata reduction
PHENIX1.14_3260phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZZZ

4zzz


Resolution: 2→71.73 Å / SU ML: 0.3782 / Cross valid method: FREE R-VALUE / σ(F): 1.88 / Phase error: 33.7505
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2647 4782 4.96 %Random selection
Rwork0.2295 91543 --
obs0.2313 96325 97.55 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 54.66 Å2
Refinement stepCycle: LAST / Resolution: 2→71.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5443 0 90 352 5885
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00285651
X-RAY DIFFRACTIONf_angle_d0.56697615
X-RAY DIFFRACTIONf_chiral_restr0.0431848
X-RAY DIFFRACTIONf_plane_restr0.0036969
X-RAY DIFFRACTIONf_dihedral_angle_d4.9683777
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.020.42241450.43922874X-RAY DIFFRACTION93.12
2.02-2.050.39711290.37173022X-RAY DIFFRACTION95.89
2.05-2.070.35861650.37942997X-RAY DIFFRACTION95.01
2.07-2.10.41561720.37963022X-RAY DIFFRACTION97.38
2.1-2.130.36661710.36633078X-RAY DIFFRACTION98.04
2.13-2.150.37781370.36633074X-RAY DIFFRACTION97.78
2.15-2.190.3971750.35413051X-RAY DIFFRACTION99.14
2.19-2.220.39011350.33573141X-RAY DIFFRACTION98.56
2.22-2.250.38571660.343054X-RAY DIFFRACTION98.38
2.25-2.290.36661470.33613115X-RAY DIFFRACTION98.43
2.29-2.330.32461520.32443082X-RAY DIFFRACTION98.9
2.33-2.370.32931830.30033042X-RAY DIFFRACTION97.67
2.37-2.420.38881380.31043081X-RAY DIFFRACTION96.96
2.42-2.470.3571680.28923001X-RAY DIFFRACTION98.11
2.47-2.520.30581680.2773117X-RAY DIFFRACTION98.12
2.52-2.580.30781580.27753008X-RAY DIFFRACTION98.11
2.58-2.640.281810.28113071X-RAY DIFFRACTION98.07
2.64-2.710.38811430.27513109X-RAY DIFFRACTION97.69
2.71-2.790.30741720.26773010X-RAY DIFFRACTION97.88
2.79-2.880.25931700.25083086X-RAY DIFFRACTION98.13
2.88-2.990.28421440.25193132X-RAY DIFFRACTION98.88
2.99-3.110.29581600.24823099X-RAY DIFFRACTION99
3.11-3.250.2881840.2343048X-RAY DIFFRACTION98.48
3.25-3.420.22571260.21653063X-RAY DIFFRACTION97.34
3.42-3.630.25131620.19633034X-RAY DIFFRACTION96.7
3.63-3.910.20291650.18493042X-RAY DIFFRACTION97.3
3.91-4.310.21711510.17383050X-RAY DIFFRACTION97.59
4.31-4.930.20441720.15913006X-RAY DIFFRACTION96.39
4.93-6.210.22011690.18933055X-RAY DIFFRACTION97.31
6.21-71.730.22521740.18032979X-RAY DIFFRACTION96.25

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