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- PDB-8u4w: The crystal structure of a helical domain deleted PARP1 in comple... -

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Basic information

Entry
Database: PDB / ID: 8u4w
TitleThe crystal structure of a helical domain deleted PARP1 in complex with isoindolinone based inhibitor.
ComponentsPoly [ADP-ribose] polymerase 1, processed C-terminus
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PARP1 / 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 / 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) / 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 / negative regulation of cGAS/STING signaling pathway / 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 / POLB-Dependent Long Patch Base Excision Repair / nucleosome binding / positive regulation of double-strand break repair via homologous recombination / SUMOylation of DNA damage response and repair proteins / protein localization to chromatin / negative regulation of innate immune response / telomere maintenance / nucleotidyltransferase activity / transforming growth factor beta receptor signaling pathway / cellular response to nerve growth factor stimulus / protein-DNA complex / mitochondrion organization / 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 / histone deacetylase binding / positive regulation of protein localization to nucleus / Formation of Incision Complex in GG-NER / cellular response to insulin stimulus / 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 / ubiquitin protein ligase binding / DNA damage response / chromatin binding / chromatin / nucleolus / protein kinase binding / apoptotic process / 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
: / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.02 Å
AuthorsMarcotte, D.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Chemmedchem / Year: 2024
Title: Discovery of Potent Isoindolinone Inhibitors that Target an Active Conformation of PARP1 Using DNA-Encoded Libraries.
Authors: McCarthy, K.A. / Marcotte, D.J. / Parelkar, S. / McKinnon, C.L. / Trammell, L.E. / Stangeland, E.L. / Jetson, R.R.
History
DepositionSep 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jun 26, 2024Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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, processed C-terminus
B: Poly [ADP-ribose] polymerase 1, processed C-terminus
C: Poly [ADP-ribose] polymerase 1, processed C-terminus
D: Poly [ADP-ribose] polymerase 1, processed C-terminus
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,7538
Polymers110,7034
Non-polymers2,0504
Water39622
1
A: Poly [ADP-ribose] polymerase 1, processed C-terminus
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1882
Polymers27,6761
Non-polymers5131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1, processed C-terminus
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1882
Polymers27,6761
Non-polymers5131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Poly [ADP-ribose] polymerase 1, processed C-terminus
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1882
Polymers27,6761
Non-polymers5131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Poly [ADP-ribose] polymerase 1, processed C-terminus
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1882
Polymers27,6761
Non-polymers5131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)37.800, 74.840, 83.450
Angle α, β, γ (deg.)109.10, 99.10, 90.58
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Poly [ADP-ribose] polymerase 1, processed C-terminus / Poly [ADP-ribose] polymerase 1 / 89-kDa form


Mass: 27675.691 Da / Num. of mol.: 4 / Mutation: Y829H
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
#2: Chemical
ChemComp-VHU / (4M)-4-(2-{4-[(3S)-1-acetylpiperidine-3-carbonyl]piperazine-1-carbonyl}-1-benzofuran-7-yl)-1H-isoindol-1-one


Mass: 512.556 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C29H28N4O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 1.99 Å3/Da / Density % sol: 38.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 35% PEG2000 MME, 0.2M KSC and 0.1M HEPES pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 8, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.02→45.31 Å / Num. obs: 16544 / % possible obs: 98.9 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 8.9
Reflection shellResolution: 3.02→3.2 Å / Rmerge(I) obs: 0.424 / Num. unique obs: 2682

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
MOLREPphasing
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.02→45.31 Å / Cor.coef. Fo:Fc: 0.897 / Cor.coef. Fo:Fc free: 0.85 / SU B: 69.326 / SU ML: 0.583 / Cross valid method: THROUGHOUT / ESU R Free: 0.641 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29154 755 4.7 %RANDOM
Rwork0.24184 ---
obs0.24416 15220 95.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 69.333 Å2
Baniso -1Baniso -2Baniso -3
1--5.41 Å22.88 Å21.71 Å2
2---0.32 Å22.9 Å2
3---2.3 Å2
Refinement stepCycle: 1 / Resolution: 3.02→45.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7333 0 152 22 7507
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0137727
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177352
X-RAY DIFFRACTIONr_angle_refined_deg1.2311.67410444
X-RAY DIFFRACTIONr_angle_other_deg1.0081.60817138
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4775927
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.03823.249354
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.107151390
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8391532
X-RAY DIFFRACTIONr_chiral_restr0.0360.2986
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.028436
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021492
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_it0.4463.493735
X-RAY DIFFRACTIONr_mcbond_other0.4463.4893734
X-RAY DIFFRACTIONr_mcangle_it0.835.2314647
X-RAY DIFFRACTIONr_mcangle_other0.835.2314648
X-RAY DIFFRACTIONr_scbond_it0.2973.5933992
X-RAY DIFFRACTIONr_scbond_other0.2973.5933992
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.5885.3885796
X-RAY DIFFRACTIONr_long_range_B_refined1.86839.888005
X-RAY DIFFRACTIONr_long_range_B_other1.86439.888004
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.02→3.098 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 61 -
Rwork0.359 1129 -
obs--95.12 %
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)
13.67890.58430.5833.67281.35923.408-0.0651-0.19390.12750.2490.13930.0623-0.0737-0.2806-0.07420.26980.0247-0.03090.2677-0.08640.056418.4838-20.9682-6.1584
22.4361-0.5638-0.21294.21991.56494.5595-0.06160.0885-0.0862-0.23770.1350.12990.0075-0.2603-0.07350.2299-0.0888-0.05580.3569-0.04850.039518.5569-52.55867.3509
35.58850.1481-0.28343.5771.31983.69170.0406-0.59880.37810.29810.02650.0685-0.205-0.0429-0.06710.39050.007-0.03960.321-0.19670.24494.5492-27.946542.2004
43.0532-0.5650.8863.46531.24815.35950.02440.6408-0.1612-0.5068-0.1665-0.06550.3785-0.12370.14220.4867-0.0375-0.03980.4554-0.2010.245727.47313.004937.0224
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A661 - 1009
2X-RAY DIFFRACTION2B661 - 1009
3X-RAY DIFFRACTION3C661 - 1009
4X-RAY DIFFRACTION4D661 - 1008

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