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- PDB-6ghk: Human PARP1 (ARTD1) - Catalytic domain in complex with inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 6ghk
TitleHuman PARP1 (ARTD1) - Catalytic domain in complex with inhibitor ME0527
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE / Inhibitor / ADP-ribosyl transferase / Protein-ligand 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 / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / 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 / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / carbohydrate biosynthetic process / regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of single strand break repair / vRNA Synthesis / NAD+-protein-serine ADP-ribosyltransferase 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 / signal transduction involved in regulation of gene expression / replication fork reversal / positive regulation of necroptotic process / ATP generation from poly-ADP-D-ribose / regulation of catalytic activity / HDR through MMEJ (alt-NHEJ) / transcription regulator activator activity / : / 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 / positive regulation of double-strand break repair via homologous recombination / protein poly-ADP-ribosylation / positive regulation of cardiac muscle hypertrophy / nuclear replication fork / negative regulation of transcription elongation by RNA polymerase II / 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 / nucleosome binding / POLB-Dependent Long Patch Base Excision Repair / SUMOylation of DNA damage response and repair proteins / protein localization to chromatin / telomere maintenance / negative regulation of innate immune response / nucleotidyltransferase activity / mitochondrion organization / cellular response to nerve growth factor stimulus / transforming growth factor beta receptor signaling pathway / nuclear estrogen receptor binding / protein-DNA complex / 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 / histone deacetylase binding / cellular response to insulin stimulus / cellular response to amyloid-beta / cellular response to UV / NAD binding / regulation of protein localization / double-strand break repair / site of double-strand break / nuclear envelope / cellular response to oxidative stress / 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 / damaged DNA binding / chromosome, telomeric region / nuclear body / DNA repair / innate immune response / negative regulation of DNA-templated transcription / apoptotic process / DNA damage response / chromatin binding / ubiquitin protein ligase binding / chromatin / nucleolus / protein kinase binding / negative regulation of transcription by RNA polymerase II / enzyme binding
Similarity search - Function
: / 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 ...: / 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 / Alpha Beta
Similarity search - Domain/homology
Chem-EZ2 / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsKarlberg, T. / Thorsell, A.G. / Lindgren, A.E.G. / Moche, M. / Brock, J. / Ekblad, T. / Spjut, S. / Elofsson, M. / Schuler, H.
CitationJournal: To Be Published
Title: Human PARP1 (ARTD1) - Catalytic domain in complex with inhibitor ME0527
Authors: Karlberg, T. / Thorsell, A.G. / Lindgren, A.E.G. / Ekblad, T. / Spjut, S. / Elofsson, M. / Schuler, H.
History
DepositionMay 8, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2024Group: 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)81,75110
Polymers80,4002
Non-polymers1,3518
Water3,747208
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,9726
Polymers40,2001
Non-polymers7725
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7804
Polymers40,2001
Non-polymers5803
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.550, 68.564, 91.813
Angle α, β, γ (deg.)90.00, 110.95, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 2
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, NAD+ ADP-ribosyltransferase
#2: Chemical ChemComp-EZ2 / ~{N}-[(1~{R})-1-(4-imidazol-1-ylphenyl)ethyl]-3-(4-oxidanylidene-1~{H}-quinazolin-2-yl)propanamide


Mass: 387.434 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H21N5O2
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 208 / 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: 2.73 Å3/Da / Density % sol: 54.87 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 22.5% PEG 3350, 0.18M ammonium sulfate, 0.09M Bis-Tris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: May 28, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.28→48.85 Å / Num. obs: 39741 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Rmerge(I) obs: 0.166 / Net I/σ(I): 11.1
Reflection shellResolution: 2.28→2.42 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.838 / Num. unique obs: 6334 / % possible all: 98.4

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4gv7

4gv7


Resolution: 2.28→48.85 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.21
RfactorNum. reflection% reflectionSelection details
Rfree0.2265 1986 5 %Random Selection
Rwork0.1869 ---
obs0.189 39736 99.71 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.28→48.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5552 0 88 208 5848
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095748
X-RAY DIFFRACTIONf_angle_d1.137756
X-RAY DIFFRACTIONf_dihedral_angle_d11.0823498
X-RAY DIFFRACTIONf_chiral_restr0.063853
X-RAY DIFFRACTIONf_plane_restr0.006983
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2773-2.33430.32561380.24452627X-RAY DIFFRACTION97
2.3343-2.39740.29361410.23652682X-RAY DIFFRACTION100
2.3974-2.46790.30371400.23132666X-RAY DIFFRACTION100
2.4679-2.54760.30431420.23042700X-RAY DIFFRACTION100
2.5476-2.63860.27851410.22752666X-RAY DIFFRACTION100
2.6386-2.74430.29511410.22942690X-RAY DIFFRACTION100
2.7443-2.86920.26421420.21272697X-RAY DIFFRACTION100
2.8692-3.02040.24421420.20532684X-RAY DIFFRACTION100
3.0204-3.20960.24321410.20512694X-RAY DIFFRACTION100
3.2096-3.45740.26931420.19312698X-RAY DIFFRACTION100
3.4574-3.80520.19781440.17222730X-RAY DIFFRACTION100
3.8052-4.35550.18821420.14732695X-RAY DIFFRACTION100
4.3555-5.48630.14471430.13912725X-RAY DIFFRACTION100
5.4863-48.86340.18741470.17142796X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 20.2579 Å / Origin y: -6.2411 Å / Origin z: 20.1888 Å
111213212223313233
T0.1849 Å20.0066 Å2-0.026 Å2-0.1448 Å2-0.0092 Å2--0.1282 Å2
L1.6542 °20.2319 °2-0.2764 °2-0.4513 °2-0.153 °2--0.4797 °2
S0.0336 Å °-0.1921 Å °0.0106 Å °0.0437 Å °-0.0355 Å °0.0157 Å °-0.0593 Å °0.0071 Å °0.0012 Å °
Refinement TLS groupSelection details: all

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