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- PDB-4r6e: Human artd1 (parp1) - catalytic domain in complex with inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 4r6e
TitleHuman artd1 (parp1) - catalytic domain in complex with inhibitor niraparib
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / ADP-RIBOSYLATION / DNA REPAIR / ADP-RIBOSYL TRANSFERASE / 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 / 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 / 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 / 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 / regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of single strand break repair / 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 / DNA ADP-ribosylation / mitochondrial DNA metabolic process / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / signal transduction involved in regulation of gene expression / replication fork reversal / positive regulation of necroptotic process / regulation of catalytic activity / ATP generation from poly-ADP-D-ribose / transcription regulator activator activity / HDR through MMEJ (alt-NHEJ) / : / positive regulation of DNA-templated transcription, elongation / NAD+ ADP-ribosyltransferase / cellular response to zinc ion / negative regulation of telomere maintenance via telomere lengthening / positive regulation of intracellular estrogen receptor signaling pathway / 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 double-strand break repair via homologous recombination / positive regulation of cardiac muscle hypertrophy / negative regulation of transcription elongation by RNA polymerase II / nuclear replication fork / site of DNA damage / NAD+-protein ADP-ribosyltransferase activity / R-SMAD binding / positive regulation of SMAD protein signal transduction / macrophage differentiation / protein autoprocessing / decidualization / NAD+ ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / POLB-Dependent Long Patch Base Excision Repair / nucleosome binding / SUMOylation of DNA damage response and repair proteins / protein localization to chromatin / telomere maintenance / negative regulation of innate immune response / nucleotidyltransferase activity / mitochondrion organization / transforming growth factor beta receptor signaling pathway / cellular response to nerve growth factor stimulus / protein-DNA complex / nuclear estrogen receptor binding / response to gamma radiation / 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 / positive regulation of protein localization to nucleus / cellular response to insulin stimulus / histone deacetylase binding / cellular response to amyloid-beta / NAD binding / cellular response to UV / regulation of protein localization / double-strand break repair / nuclear envelope / cellular response to oxidative stress / site of double-strand break / positive regulation of canonical NF-kappaB signal transduction / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / transcription by RNA polymerase II / chromosome, telomeric region / damaged DNA binding / nuclear body / innate immune response / DNA repair / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / DNA damage response / chromatin binding / chromatin / nucleolus / protein kinase binding / negative regulation of transcription by RNA polymerase II / enzyme binding
Similarity search - Function
Poly(ADP-ribose) polymerase, regulatory domain / Poly(ADP-ribose) Polymerase; domain 1 / : / PADR1, N-terminal helical domain / PADR1 domain profile. / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / PADR1 domain, zinc ribbon fold / PADR1 ...Poly(ADP-ribose) polymerase, regulatory domain / Poly(ADP-ribose) Polymerase; domain 1 / : / 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 / Up-down Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-3JD / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsKarlberg, T. / Thorsell, A.G. / Brock, J. / Schuler, H.
CitationJournal: J.Med.Chem. / Year: 2017
Title: Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors.
Authors: Thorsell, A.G. / Ekblad, T. / Karlberg, T. / Low, M. / Pinto, A.F. / Tresaugues, L. / Moche, M. / Cohen, M.S. / Schuler, H.
History
DepositionAug 25, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 9, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 18, 2017Group: Database references
Revision 1.2Aug 24, 2022Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / database_2 / struct_ref_seq_dif / struct_site
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.year / _citation_author.identifier_ORCID / _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 1.3Sep 20, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)162,74215
Polymers160,8004
Non-polymers1,94211
Water2,774154
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7084
Polymers40,2001
Non-polymers5093
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7084
Polymers40,2001
Non-polymers5093
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7084
Polymers40,2001
Non-polymers5093
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6163
Polymers40,2001
Non-polymers4162
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.400, 108.630, 142.200
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: 40199.949 Da / Num. of mol.: 4 / Fragment: CATALYTIC DOMAIN (UNP residues 662-1011)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADPRT, PARP1, PPOL / Plasmid: pNIC-CH / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2(DE3) / References: UniProt: P09874, NAD+ ADP-ribosyltransferase
#2: Chemical
ChemComp-3JD / 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide / Niraparib / Niraparib


Mass: 320.388 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H20N4O / Comment: medication, anticancer*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 154 / 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: 2.51 Å3/Da / Density % sol: 50.94 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 20% PEG-3350, 0.16M Ammonium Sulfate, 0.08M Bis-Tris, 0.001M Niraparib, pH 5.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 30, 2014 / Details: mirrors
RadiationMonochromator: Double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.2→86.32 Å / Num. all: 82734 / Num. obs: 82734 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 13.2 % / Biso Wilson estimate: 45.1 Å2 / Rmerge(I) obs: 0.087 / Net I/σ(I): 18.4
Reflection shellResolution: 2.2→2.26 Å / Redundancy: 13.7 % / Rmerge(I) obs: 0.722 / Mean I/σ(I) obs: 4 / Num. unique all: 6064 / % possible all: 100

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Processing

Software
NameVersionClassification
GDAdata collection
PHASERphasing
BUSTER2.11.5refinement
xia2data reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4GV7

4gv7


Resolution: 2.2→86.3 Å / Cor.coef. Fo:Fc: 0.9437 / Cor.coef. Fo:Fc free: 0.9305 / SU R Cruickshank DPI: 0.243 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2179 4123 4.99 %RANDOM
Rwork0.2022 ---
obs0.203 82654 100 %-
all-82654 --
Displacement parametersBiso mean: 58.05 Å2
Baniso -1Baniso -2Baniso -3
1-2.5667 Å20 Å20 Å2
2---2.5674 Å20 Å2
3---0.0007 Å2
Refine analyzeLuzzati coordinate error obs: 0.359 Å
Refinement stepCycle: LAST / Resolution: 2.2→86.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10990 0 134 154 11278
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111347HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0615318HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5334SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes320HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1601HARMONIC5
X-RAY DIFFRACTIONt_it11347HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion3.09
X-RAY DIFFRACTIONt_other_torsion3.08
X-RAY DIFFRACTIONt_chiral_improper_torsion1464SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact12189SEMIHARMONIC4
LS refinement shellResolution: 2.2→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2643 271 4.48 %
Rwork0.2377 5780 -
all0.2389 6051 -
obs-6051 99.99 %
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)
11.55970.20790.25520.961-0.24592.72870.0269-0.1267-0.109-0.05770.08510.07350.41450.076-0.112-0.10040.0393-0.0503-0.15790.0324-0.1457-75.221421.377730.0224
21.8824-0.2080.18462.3028-0.08121.26990.09460.1936-0.1553-0.1640.0068-0.03440.17770.2403-0.1014-0.16180.0571-0.0001-0.0594-0.0701-0.1573-71.197750.031467.1391
32.3844-0.5968-0.20652.2843-0.45521.66470.0846-0.070.01120.02030.00140.0599-0.1859-0.0546-0.086-0.2121-0.0146-0.0015-0.0750.0721-0.155-60.8567-2.266661.0955
43.81711.544-0.68913.0318-0.07812.46610.1669-0.35030.05360.5654-0.3847-0.0404-0.5497-0.44150.2178-0.19950.1315-0.1498-0.1262-0.1687-0.2548-117.28935.2625.2005
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|661 - A|1010 }A661 - 1010
2X-RAY DIFFRACTION2{ B|662 - B|1011 }B662 - 1011
3X-RAY DIFFRACTION3{ C|661 - C|1010 }C661 - 1010
4X-RAY DIFFRACTION4{ D|663 - D|1010 }D663 - 1010

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