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- PDB-4l6s: PARP complexed with benzo[1,4]oxazin-3-one inhibitor -

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Basic information

Entry
Database: PDB / ID: 4l6s
TitlePARP complexed with benzo[1,4]oxazin-3-one inhibitor
ComponentsPoly [ADP-ribose] polymerase 1
Keywordstransferase/transferase inhibitor / DNA single-strand break repair sensitize tumors / DNA repair enzyme / DRD / 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 / 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
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-1WQ / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsDougan, D.R. / Mol, C.D. / Lawson, J.D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors
Authors: Gangloff, A.R. / Brown, J. / de Jong, R. / Dougan, D.R. / Grimshaw, C.E. / Hixon, M. / Jennings, A. / Kamran, R. / Kiryanov, A. / O'Connell, S. / Taylor, E. / Vu, P.
History
DepositionJun 12, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 12, 2014Group: Structure summary
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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

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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)79,7284
Polymers78,9902
Non-polymers7382
Water5,350297
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8642
Polymers39,4951
Non-polymers3691
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8642
Polymers39,4951
Non-polymers3691
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.525, 93.045, 165.193
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: 39495.195 Da / Num. of mol.: 2 / Fragment: unp residues 662-1011 / Mutation: V762A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: BL21DE3 / Gene: ADPRT, PARP 1, PARP1, PPOL / Production host: Escherichia coli (E. coli) / References: UniProt: P09874, NAD+ ADP-ribosyltransferase
#2: Chemical ChemComp-1WQ / (2S)-6-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one


Mass: 368.857 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H21ClN2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 297 / 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: 2.36 Å3/Da / Density % sol: 47.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 1.4M tri-sodium citrate, 0.1M HEPES , pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9926 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 7, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9926 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. all: 42109 / Num. obs: 35669 / % possible obs: 89.7 %
Reflection shellResolution: 2.15→2.2 Å / % possible all: 48.9

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Processing

Software
NameVersionClassification
HKL-2000data collection
AMoREphasing
REFMAC5.7.0025refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→30 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.93 / SU B: 12.187 / SU ML: 0.151 / Cross valid method: THROUGHOUT / ESU R: 0.278 / ESU R Free: 0.223 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.23402 1814 5 %RANDOM
Rwork0.16357 ---
obs0.16696 34271 92.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.445 Å2
Baniso -1Baniso -2Baniso -3
1-0.71 Å20 Å20 Å2
2--1.67 Å20 Å2
3----2.37 Å2
Refinement stepCycle: LAST / Resolution: 2.2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5532 0 52 297 5881
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0195705
X-RAY DIFFRACTIONr_bond_other_d0.0010.022
X-RAY DIFFRACTIONr_angle_refined_deg1.5671.9917702
X-RAY DIFFRACTIONr_angle_other_deg1.17234
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7395700
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.76225.164244
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.737151060
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7021522
X-RAY DIFFRACTIONr_chiral_restr0.1040.2858
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214226
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 110 -
Rwork0.211 1603 -
obs--61.18 %
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)
10.2799-0.0205-0.13140.10460.10210.32530.01720.01250.01150.0271-0.03530.02990.00280.04530.01810.0107-0.01580.00740.0538-0.00080.019215.0155-2.8832-5.2222
20.1468-0.0397-0.01150.15350.32560.75180.0245-0.0054-0.0416-0.0237-0.0001-0.0092-0.0539-0.0282-0.02430.02710.0019-0.00440.0148-0.01080.0265-6.0501-20.4354-38.1506
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A662 - 1011
2X-RAY DIFFRACTION1A1100
3X-RAY DIFFRACTION2B662 - 1011
4X-RAY DIFFRACTION2B1100

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