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- PDB-4rv6: Human ARTD1 (PARP1) catalytic domain in complex with inhibitor Ru... -

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Basic information

Entry
Database: PDB / ID: 4rv6
TitleHuman ARTD1 (PARP1) catalytic domain in complex with inhibitor Rucaparib
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTransferase/Transferase inhibitor / ADP-ribosyl Transferase / ADP-ribosylation / 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 / NAD+-histone H2BE35 glutamate 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 myofibroblast differentiation / regulation of base-excision repair / NAD+-histone H2BS6 serine ADP-ribosyltransferase activity / NAD+-histone H3S10 serine ADP-ribosyltransferase activity / NAD+-histone H2BE35 glutamate 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) / 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 / NAD+-protein-aspartate ADP-ribosyltransferase activity / mitochondrial DNA repair / protein poly-ADP-ribosylation / positive regulation of intracellular estrogen receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / NAD+-protein-glutamate ADP-ribosyltransferase activity / 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 / transcription by RNA polymerase II / damaged DNA binding / positive regulation of canonical NF-kappaB signal transduction / 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
Rucaparib / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.19 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
DepositionNov 25, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 9, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.2Sep 5, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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
C: Poly [ADP-ribose] polymerase 1
D: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,77112
Polymers157,5484
Non-polymers1,2238
Water543
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9034
Polymers39,3871
Non-polymers5153
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9034
Polymers39,3871
Non-polymers5153
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4832
Polymers39,3871
Non-polymers961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4832
Polymers39,3871
Non-polymers961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)93.631, 85.099, 101.945
Angle α, β, γ (deg.)90.00, 100.97, 90.00
Int Tables number3
Space group name H-MP121

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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: 39387.078 Da / Num. of mol.: 4 / Fragment: Catalytic PARP 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-Bsa4 / 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.: 6 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-RPB / Rucaparib


Mass: 323.364 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18FN3O / Comment: anticancer, inhibitor*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsAUTHORS STATE THAT RESIDUE 762 CORRESPONDS TO A NATURAL VARIATION (V762A) AT THIS POSITION.

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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: 2.53 Å3/Da / Density % sol: 51.4 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.9
Details: 27% PEG3350, 0.2 M Ammonium Sulfate, 0.1 M Bis-Tris, 1mM Rucaparib, pH 5.9, 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 Monochromator (Si-111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 3.19→47.95 Å / Num. obs: 26435 / % possible obs: 99.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.9 % / Biso Wilson estimate: 73.31 Å2 / Rmerge(I) obs: 0.193 / Net I/σ(I): 7.9
Reflection shellResolution: 3.19→3.83 Å / Rmerge(I) obs: 0.924 / Mean I/σ(I) obs: 1.5 / % possible all: 98.8

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Processing

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

4gv7


Resolution: 3.19→37.94 Å / Cor.coef. Fo:Fc: 0.9283 / Cor.coef. Fo:Fc free: 0.9081 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2123 1322 5 %RANDOM
Rwork0.1811 ---
obs0.1827 26435 99.92 %-
Displacement parametersBiso mean: 83 Å2
Baniso -1Baniso -2Baniso -3
1-9.5745 Å20 Å20.7526 Å2
2---0.4645 Å20 Å2
3----9.11 Å2
Refine analyzeLuzzati coordinate error obs: 0.618 Å
Refinement stepCycle: LAST / Resolution: 3.19→37.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10946 0 78 3 11027
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0111230HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1715159HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5299SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes307HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1584HARMONIC5
X-RAY DIFFRACTIONt_it11230HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.72
X-RAY DIFFRACTIONt_other_torsion3.65
X-RAY DIFFRACTIONt_chiral_improper_torsion1451SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact12877SEMIHARMONIC4
LS refinement shellResolution: 3.19→3.32 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2537 149 5.02 %
Rwork0.2249 2820 -
all0.2265 2969 -
obs--99.92 %
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)
13.44930.3844-0.32452.36570.04180.84050.06310.15010.614-0.2674-0.06370.1751-0.06840.04070.0006-0.25590.1041-0.0767-0.09590.0514-0.021195.8811-0.3318125.0742
23.4627-0.1074-0.18393.2297-0.05960.55030.07420.0482-0.73-0.1579-0.08820.00020.12220.05190.014-0.26650.0957-0.1257-0.0946-0.0294-0.019952.57195.5403125.6828
34.3708-0.09710.60362.4533-0.10821.2482-0.0710.0961.0975-0.04280.0126-0.4724-0.180.21930.0585-0.3378-0.0133-0.0343-0.2829-0.05090.225149.179141.1043125.786
43.9329-0.5319-0.71923.89040.49471.6155-0.29630.2061-1.2538-0.0389-0.07670.97940.1415-0.18260.373-0.41730.03060.0571-0.3227-0.0430.472799.7288-35.8497125.8546
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|662 - A|1010 }A662 - 1010
2X-RAY DIFFRACTION2{ B|662 - B|1010 }B662 - 1010
3X-RAY DIFFRACTION3{ C|662 - C|1010 }C662 - 1010
4X-RAY DIFFRACTION4{ D|662 - D|1010 }D662 - 1010

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