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- PDB-4r5w: Human artd1 (parp1) - catalytic domain in complex with inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 4r5w
TitleHuman artd1 (parp1) - catalytic domain in complex with inhibitor xav939
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


positive regulation of myofibroblast differentiation / regulation of base-excision repair / NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis / positive regulation of single strand break repair ...positive regulation of myofibroblast differentiation / regulation of base-excision repair / NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / negative regulation of ATP biosynthetic process / NAD+-protein-tyrosine ADP-ribosyltransferase activity / NAD+-protein-histidine ADP-ribosyltransferase activity / regulation of circadian sleep/wake cycle, non-REM sleep / vRNA Synthesis / positive regulation of single strand break repair / carbohydrate biosynthetic process / NAD+-protein-serine ADP-ribosyltransferase activity / regulation of catalytic activity / negative regulation of adipose tissue development / NAD DNA ADP-ribosyltransferase activity / DNA ADP-ribosylation / mitochondrial DNA metabolic process / regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / replication fork reversal / ATP generation from poly-ADP-D-ribose / positive regulation of necroptotic process / transcription regulator activator activity / HDR through MMEJ (alt-NHEJ) / NAD+-histone H2BE35 glutamate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / positive regulation of DNA-templated transcription, elongation / signal transduction involved in regulation of gene expression / NAD+ ADP-ribosyltransferase / cellular response to zinc ion / negative regulation of telomere maintenance via telomere lengthening / protein auto-ADP-ribosylation / positive regulation of intracellular estrogen receptor signaling pathway / NAD+-protein-aspartate ADP-ribosyltransferase activity / mitochondrial DNA repair / protein poly-ADP-ribosylation / negative regulation of cGAS/STING signaling pathway / response to aldosterone / positive regulation of mitochondrial depolarization / positive regulation of cardiac muscle hypertrophy / NAD+-protein mono-ADP-ribosyltransferase activity / nuclear replication fork / R-SMAD binding / negative regulation of transcription elongation by RNA polymerase II / protein autoprocessing / site of DNA damage / macrophage differentiation / NAD+ poly-ADP-ribosyltransferase activity / decidualization / Transferases; Glycosyltransferases; Pentosyltransferases / positive regulation of SMAD protein signal transduction / 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 / nucleosome binding / protein localization to chromatin / nucleotidyltransferase activity / telomere maintenance / transforming growth factor beta receptor signaling pathway / negative regulation of innate immune response / nuclear estrogen receptor binding / response to gamma radiation / mitochondrion organization / Downregulation of SMAD2/3:SMAD4 transcriptional activity / cellular response to nerve growth factor stimulus / DNA Damage Recognition in GG-NER / protein-DNA complex / protein modification process / positive regulation of protein localization to nucleus / Dual Incision in GG-NER / histone deacetylase binding / Formation of Incision Complex in GG-NER / cellular response to insulin stimulus / cellular response to amyloid-beta / NAD binding / cellular response to UV / nuclear envelope / double-strand break repair / regulation of protein localization / site of double-strand break / cellular response to oxidative stress / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / positive regulation of canonical NF-kappaB signal transduction / transcription by RNA polymerase II / damaged DNA binding / chromosome, telomeric region / nuclear body / innate immune response / DNA repair / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / DNA damage response / chromatin binding / protein kinase binding / chromatin / nucleolus / 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 / Poly [ADP-ribose] polymerase / PADR1 domain / PADR1 domain superfamily / : / PADR1 domain, zinc ribbon fold / PADR1, N-terminal helical domain / PADR1 domain profile. / PADR1 ...Poly(ADP-ribose) polymerase, regulatory domain / Poly(ADP-ribose) Polymerase; domain 1 / 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. / 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-XAV / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.84 Å
AuthorsKarlberg, T. / Thorsell, A.G. / 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 22, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 18, 2017Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Aug 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 1.4Sep 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

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)81,69711
Polymers80,4002
Non-polymers1,2979
Water19811
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,9937
Polymers40,2001
Non-polymers7936
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7044
Polymers40,2001
Non-polymers5043
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.525, 67.662, 91.165
Angle α, β, γ (deg.)90.00, 111.28, 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 / 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-XAV / 2-[4-(trifluoromethyl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol


Mass: 312.310 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H11F3N2OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 11 / 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: 2.66 Å3/Da / Density % sol: 53.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 21% PEG-3350, 0.17M Ammonium Sulfate, 0.09M Bis-Tris, 1mM XAV939, pH 5.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.91841 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Jun 3, 2014 / Details: mirrors
RadiationMonochromator: Double crystal (Si-111) monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.84→48.5 Å / Num. obs: 20249 / % possible obs: 99.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.9 % / Biso Wilson estimate: 71.39 Å2 / Rmerge(I) obs: 0.168 / Net I/σ(I): 10.1
Reflection shellResolution: 2.84→3.01 Å / Rmerge(I) obs: 0.921 / Mean I/σ(I) obs: 1.8 / % possible all: 98.3

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Processing

Software
NameVersionClassification
MAR345data collection
PHASERphasing
BUSTER2.11.5refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4GV7

4gv7


Resolution: 2.84→48.46 Å / Cor.coef. Fo:Fc: 0.9188 / Cor.coef. Fo:Fc free: 0.8546 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2451 1013 5 %RANDOM
Rwork0.1923 ---
obs0.1949 20249 99.22 %-
all-20408 --
Displacement parametersBiso mean: 49.28 Å2
Baniso -1Baniso -2Baniso -3
1-0.023 Å20 Å2-0.33 Å2
2---8.1495 Å20 Å2
3---8.1265 Å2
Refine analyzeLuzzati coordinate error obs: 0.371 Å
Refinement stepCycle: LAST / Resolution: 2.84→48.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5556 0 77 11 5644
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015738HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.177750HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2684SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes154HARMONIC2
X-RAY DIFFRACTIONt_gen_planes806HARMONIC5
X-RAY DIFFRACTIONt_it5738HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.92
X-RAY DIFFRACTIONt_other_torsion3.4
X-RAY DIFFRACTIONt_chiral_improper_torsion736SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact6293SEMIHARMONIC4
LS refinement shellResolution: 2.84→2.98 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2466 141 5.01 %
Rwork0.2345 2672 -
all0.2351 2813 -
obs-2813 99.22 %
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)
11.29570.0418-0.01581.8794-0.00891.5505-0.0035-0.0532-0.02730.1638-0.00130.0992-0.0135-0.2250.0048-0.1495-0.0248-0.0042-0.0806-0.0249-0.0706-18.7029-8.9618-20.5941
20.85570.3139-0.09221.4923-0.76421.80680.0655-0.10990.03350.1324-0.0031-0.055-0.22740.2597-0.0624-0.0872-0.02670.031-0.0659-0.0179-0.096517.6242-3.7586-24.1646
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|661 - A|1013 }A661 - 1013
2X-RAY DIFFRACTION2{ B|661 - B|1017 }B661 - 1017

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