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- PDB-5kpq: Structure of human PARP1 catalytic domain bound to a quinazoline-... -

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Basic information

Entry
Database: PDB / ID: 5kpq
TitleStructure of human PARP1 catalytic domain bound to a quinazoline-2,4(1H,3H)-dione inhibitor
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / Complex / 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 / 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 / positive regulation of protein localization to nucleus / Formation of Incision Complex in GG-NER / 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. / 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-6X2 / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsCao, R. / Wang, Y.L. / Zhou, J. / Huang, N. / Xu, B.L.
Funding support China, 1items
OrganizationGrant numberCountry
Special Funds for National Public Benefit Research Institute2013CHX16 China
CitationJournal: To Be Published
Title: Structure of human PARP1 catalytic domain bound to a quinazoline-2,4(1H,3H)-dione inhibitor
Authors: Cao, R. / Wang, Y.L. / Zhou, J. / Huang, N. / Xu, B.L.
History
DepositionJul 5, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 14, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: 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)79,2154
Polymers78,3382
Non-polymers8772
Water1,06359
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,6072
Polymers39,1691
Non-polymers4381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,6072
Polymers39,1691
Non-polymers4381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.628, 92.465, 163.847
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / NAD(+) ADP-ribosyltransferase 1 / ...PARP-1 / ADP-ribosyltransferase diphtheria toxin-like 1 / ARTD1 / NAD(+) ADP-ribosyltransferase 1 / ADPRT 1 / Poly[ADP-ribose] synthase 1


Mass: 39168.809 Da / Num. of mol.: 2 / Fragment: catalytic domain, UNP residues 662-1011 / Mutation: V762A
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
#2: Chemical ChemComp-6X2 / 1-[[4-fluoranyl-3-[(3R)-3-methyl-4-propyl-piperazin-1-yl]carbonyl-phenyl]methyl]quinazoline-2,4-dione


Mass: 438.495 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H27FN4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 59 / Source method: isolated from a natural source / Formula: H2O

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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: 2.35 Å3/Da / Density % sol: 47.71 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 2.5M AMMONIUM SULFATE, 100mM TRIS

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 10, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.55→92.35 Å / Num. obs: 24926 / % possible obs: 99.9 % / Redundancy: 11.8 % / Net I/σ(I): 23.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0123refinement
iMOSFLMdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4L6S

4l6s


Resolution: 2.55→81.92 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.902 / SU B: 14.583 / SU ML: 0.313 / Cross valid method: THROUGHOUT / ESU R: 1.612 / ESU R Free: 0.36 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28195 1199 4.9 %RANDOM
Rwork0.23289 ---
obs0.23537 23476 99.19 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 58.227 Å2
Baniso -1Baniso -2Baniso -3
1-3.33 Å2-0 Å20 Å2
2--1.26 Å2-0 Å2
3----4.6 Å2
Refinement stepCycle: LAST / Resolution: 2.55→81.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5490 0 64 59 5613
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0195720
X-RAY DIFFRACTIONr_bond_other_d0.0030.025586
X-RAY DIFFRACTIONr_angle_refined_deg1.1641.9927724
X-RAY DIFFRACTIONr_angle_other_deg0.9863.00412924
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8135698
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.58625.203246
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.967151062
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.261522
X-RAY DIFFRACTIONr_chiral_restr0.070.2860
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0216348
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021218
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.025.7722804
X-RAY DIFFRACTIONr_mcbond_other2.0165.7712803
X-RAY DIFFRACTIONr_mcangle_it3.5068.6493498
X-RAY DIFFRACTIONr_mcangle_other3.5068.6513499
X-RAY DIFFRACTIONr_scbond_it1.7755.9322916
X-RAY DIFFRACTIONr_scbond_other1.7755.9322917
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.168.7944227
X-RAY DIFFRACTIONr_long_range_B_refined5.85344.1676184
X-RAY DIFFRACTIONr_long_range_B_other5.84844.1656181
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.55→2.616 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 69 -
Rwork0.299 1696 -
obs--99.27 %

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