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- PDB-7cmw: Complex structure of PARP1 catalytic domain with pamiparib -

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Entry
Database: PDB / ID: 7cmw
TitleComplex structure of PARP1 catalytic domain with pamiparib
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsANTITUMOR PROTEIN / PARP1 / pamiparib / BGB-290 / transferase
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-DS9 / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsFeng, Y.C. / Peng, H. / Hong, Y. / Liu, Y.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.
Authors: Wang, H. / Ren, B. / Liu, Y. / Jiang, B. / Guo, Y. / Wei, M. / Luo, L. / Kuang, X. / Qiu, M. / Lv, L. / Xu, H. / Qi, R. / Yan, H. / Xu, D. / Wang, Z. / Huo, C.X. / Zhu, Y. / Zhao, Y. / Wu, Y. ...Authors: Wang, H. / Ren, B. / Liu, Y. / Jiang, B. / Guo, Y. / Wei, M. / Luo, L. / Kuang, X. / Qiu, M. / Lv, L. / Xu, H. / Qi, R. / Yan, H. / Xu, D. / Wang, Z. / Huo, C.X. / Zhu, Y. / Zhao, Y. / Wu, Y. / Qin, Z. / Su, D. / Tang, T. / Wang, F. / Sun, X. / Feng, Y. / Peng, H. / Wang, X. / Gao, Y. / Liu, Y. / Gong, W. / Yu, F. / Liu, X. / Wang, L. / Zhou, C.
History
DepositionJul 29, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 16, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 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

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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)80,0377
Polymers79,1652
Non-polymers8735
Water1,47782
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9733
Polymers39,5821
Non-polymers3902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area270 Å2
ΔGint-0 kcal/mol
Surface area16480 Å2
MethodPISA
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0654
Polymers39,5821
Non-polymers4833
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area300 Å2
ΔGint-1 kcal/mol
Surface area16180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.798, 92.427, 164.495
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
12
22
13
23
33

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111chain 'A'A662 - 1011
211chain 'B'B662 - 1011
112chain 'C'C1
212chain 'D'D2
113chain 'E'E1
213chain 'F'F1
313chain 'L'L1

NCS ensembles :
ID
1
2
3

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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: 39582.277 Da / Num. of mol.: 2 / Mutation: V762A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P09874, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical ChemComp-DS9 / (2R)-14-fluoro-2-methyl-6,9,10,19-tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen-11-one


Mass: 298.315 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H15FN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / 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: 2.32 Å3/Da / Density % sol: 46.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 2.2 M DL-malic acid pH 7.0, 0.1 M BIS-TRIS propane pH 7.0

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 11, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 20133 / % possible obs: 95.2 % / Redundancy: 5.7 % / Biso Wilson estimate: 18.18 Å2 / Rmerge(I) obs: 0.205 / Χ2: 0.918 / Net I/σ(I): 7.4
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.522 / Mean I/σ(I) obs: 4.8 / Num. unique obs: 2029 / Χ2: 0.952 / % possible all: 97.5

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HHY

4hhy


Resolution: 2.7→47.16 Å / SU ML: 0.2724 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.4965
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2583 1868 10 %Random selection
Rwork0.2038 16812 --
obs0.2093 18680 89.84 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 18.49 Å2
Refinement stepCycle: LAST / Resolution: 2.7→47.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5504 0 62 82 5648
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00585675
X-RAY DIFFRACTIONf_angle_d1.14677669
X-RAY DIFFRACTIONf_chiral_restr0.0595852
X-RAY DIFFRACTIONf_plane_restr0.0067976
X-RAY DIFFRACTIONf_dihedral_angle_d26.0362162
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.770.32041230.23691111X-RAY DIFFRACTION78.55
2.77-2.850.27951380.2471232X-RAY DIFFRACTION87.76
2.85-2.950.3061440.23581302X-RAY DIFFRACTION92.22
2.95-3.050.29621460.23991313X-RAY DIFFRACTION93.23
3.05-3.170.28821500.22751351X-RAY DIFFRACTION94.11
3.17-3.320.30111450.21841302X-RAY DIFFRACTION92.76
3.32-3.490.27361470.21461322X-RAY DIFFRACTION92.33
3.49-3.710.24651470.20261322X-RAY DIFFRACTION91.58
3.71-40.26191430.19411290X-RAY DIFFRACTION90.41
4-4.40.21191450.1641304X-RAY DIFFRACTION90.45
4.4-5.040.19591440.16221295X-RAY DIFFRACTION90.16
5.04-6.340.25061510.20181356X-RAY DIFFRACTION91.61
6.34-47.160.23171450.19021312X-RAY DIFFRACTION83.5

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