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- PDB-4hhy: Crystal structure of PARP catalytic domain in complex with novel ... -

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Basic information

Entry
Database: PDB / ID: 4hhy
TitleCrystal structure of PARP catalytic domain in complex with novel inhibitors
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Polymerase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of myofibroblast differentiation / regulation of base-excision repair / NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis ...positive regulation of myofibroblast differentiation / regulation of base-excision repair / NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis / positive regulation of single strand break repair / carbohydrate biosynthetic process / NAD+-protein-serine ADP-ribosyltransferase activity / regulation of catalytic 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 / HDR through MMEJ (alt-NHEJ) / positive regulation of DNA-templated transcription, elongation / signal transduction involved in regulation of gene expression / NAD+ ADP-ribosyltransferase / cellular response to zinc ion / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / NAD+-protein-aspartate ADP-ribosyltransferase activity / mitochondrial DNA repair / protein poly-ADP-ribosylation / positive regulation of intracellular estrogen receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / NAD+-protein-glutamate ADP-ribosyltransferase activity / response to aldosterone / positive regulation of mitochondrial depolarization / positive regulation of cardiac muscle hypertrophy / NAD+-protein mono-ADP-ribosyltransferase activity / R-SMAD binding / nuclear replication fork / negative regulation of transcription elongation by RNA polymerase II / protein autoprocessing / site of DNA damage / macrophage differentiation / NAD+ poly-ADP-ribosyltransferase activity / decidualization / Transferases; Glycosyltransferases; Pentosyltransferases / positive regulation of SMAD protein signal transduction / 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 / 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 / Downregulation of SMAD2/3:SMAD4 transcriptional activity / cellular response to nerve growth factor stimulus / DNA Damage Recognition in GG-NER / protein-DNA complex / protein modification process / positive regulation of protein localization to nucleus / Dual Incision in GG-NER / histone deacetylase binding / Formation of Incision Complex in GG-NER / cellular response to insulin stimulus / cellular response to amyloid-beta / NAD binding / 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 / RNA polymerase II-specific DNA-binding transcription factor binding / transcription by RNA polymerase II / damaged DNA binding / positive regulation of canonical NF-kappaB signal transduction / chromosome, telomeric region / 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, regulatory domain / Poly(ADP-ribose) Polymerase; domain 1 / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / : / PADR1 domain, zinc ribbon fold / PADR1, N-terminal helical domain / PADR1 domain profile. / PADR1 ...Poly(ADP-ribose) polymerase, regulatory domain / Poly(ADP-ribose) Polymerase; domain 1 / 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 / Up-down Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-15R / DI(HYDROXYETHYL)ETHER / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3637 Å
AuthorsLiu, Q.F. / Chen, T.T. / Xu, Y.C.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors.
Authors: Ye, N. / Chen, C.H. / Chen, T. / Song, Z. / He, J.X. / Huan, X.J. / Song, S.S. / Liu, Q. / Chen, Y. / Ding, J. / Xu, Y. / Miao, Z.H. / Zhang, A.
History
DepositionOct 10, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2013Group: Database references
Revision 1.2Sep 20, 2023Group: 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 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)160,93811
Polymers158,3214
Non-polymers2,6177
Water1,51384
1
C: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,1602
Polymers39,5801
Non-polymers5801
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
D: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,1602
Polymers39,5801
Non-polymers5801
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3624
Polymers39,5801
Non-polymers7823
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,2563
Polymers39,5801
Non-polymers6762
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.797, 107.549, 143.107
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: 39580.262 Da / Num. of mol.: 4 / Fragment: UNP Residues 660-1101
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADPRT, PARP1, PPOL / Plasmid: Pgex-6p-1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P09874, NAD+ ADP-ribosyltransferase
#2: Chemical
ChemComp-15R / (9aR)-1-[(1-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl}piperidin-4-yl)carbonyl]-1,2,3,8,9,9a-hexahydro-7H-benzo[de][1,7]naphthyridin-7-one


Mass: 579.621 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H30FN5O4
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 84 / Source method: isolated from a natural source / Formula: H2O
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

CrystalDensity Matthews: 2.52 Å3/Da / Density % sol: 51.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.1M TRIS pH 8.0, 1% PEG400, 1.9M (NH4)2SO4, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.979 Å
DetectorType: ADSC Quantum Q315r / Detector: CCD / Date: Mar 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.28→43.61 Å / Num. obs: 137838 / % possible obs: 97.5 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 52.413 Å2 / Rmerge(I) obs: 0.069 / Net I/σ(I): 12.92
Reflection shell
Resolution (Å)Highest resolution (Å)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2.28-2.420.72197.3
2.42-2.580.4223.361100
2.58-2.790.2645.08192.8
2.79-3.060.149.141100
3.06-3.410.07316.171100
3.41-3.940.05622.18191
3.94-4.820.03928.99199.8
4.82-6.780.03531.041100
6.780.03134.86196.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å43.61 Å
Translation2.5 Å43.61 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASER2.3.0phasing
PHENIX1.8_1069refinement
PDB_EXTRACT3.11data extraction
Blu-Icedata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3GJW

3gjw


Resolution: 2.3637→43.606 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.39 / σ(F): 1.34 / Phase error: 32.76 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2992 3288 5.07 %
Rwork0.2373 --
obs0.2404 64828 97.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.4082 Å2
Refinement stepCycle: LAST / Resolution: 2.3637→43.606 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10448 0 189 84 10721
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00910852
X-RAY DIFFRACTIONf_angle_d1.39514695
X-RAY DIFFRACTIONf_dihedral_angle_d20.7544100
X-RAY DIFFRACTIONf_chiral_restr0.0911650
X-RAY DIFFRACTIONf_plane_restr0.0051865
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3637-2.3990.41081500.32052654X-RAY DIFFRACTION99
2.399-2.43650.35861690.29472676X-RAY DIFFRACTION100
2.4365-2.47640.33371320.28762695X-RAY DIFFRACTION100
2.4764-2.51910.33661410.27972708X-RAY DIFFRACTION100
2.5191-2.56490.30851400.25782707X-RAY DIFFRACTION100
2.5649-2.61430.38231510.28112697X-RAY DIFFRACTION100
2.6143-2.66760.34081410.29962610X-RAY DIFFRACTION98
2.6676-2.72560.40481310.3062151X-RAY DIFFRACTION80
2.7256-2.7890.38031310.30432709X-RAY DIFFRACTION100
2.789-2.85870.36041390.28142722X-RAY DIFFRACTION100
2.8587-2.9360.36811570.28062694X-RAY DIFFRACTION100
2.936-3.02240.33931460.28642707X-RAY DIFFRACTION100
3.0224-3.11990.36171320.26742739X-RAY DIFFRACTION100
3.1199-3.23140.30041500.26382730X-RAY DIFFRACTION100
3.2314-3.36070.32521430.25642726X-RAY DIFFRACTION100
3.3607-3.51360.2941290.24332521X-RAY DIFFRACTION92
3.5136-3.69880.35231690.26122701X-RAY DIFFRACTION100
3.6988-3.93040.27771230.23252415X-RAY DIFFRACTION88
3.9304-4.23360.24881590.20332733X-RAY DIFFRACTION100
4.2336-4.65920.24181330.18012786X-RAY DIFFRACTION100
4.6592-5.33240.24071330.1822788X-RAY DIFFRACTION100
5.3324-6.71430.27571470.23522813X-RAY DIFFRACTION100
6.7143-43.6130.23641420.19722858X-RAY DIFFRACTION97

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