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- PDB-7ont: PARP1 catalytic domain in complex with a selective pyridine carbo... -

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Entry
Database: PDB / ID: 7ont
TitlePARP1 catalytic domain in complex with a selective pyridine carboxamide-based inhibitor (compound 22)
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE / PARP inhibitor / selectivity / structure-based drug design / synthetic lethal therapy / oncology
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
: / 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. / 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
Chem-VKQ / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.853 Å
AuthorsSchimpl, M. / Balazs, A. / Barratt, D. / Bista, M. / Chuba, M. / Degorce, S.L. / Di Fruscia, P. / Embrey, K. / Ghosh, A. / Gill, S. ...Schimpl, M. / Balazs, A. / Barratt, D. / Bista, M. / Chuba, M. / Degorce, S.L. / Di Fruscia, P. / Embrey, K. / Ghosh, A. / Gill, S. / Gunnarsson, A. / Hande, S. / Hemsley, P. / Heightman, T.D. / Illuzzi, G. / Lane, J. / Larner, C. / Leo, E. / Madin, A. / Martin, S. / McWilliams, L. / Orme, J. / Pachl, F. / Packer, M.J. / Pike, A. / Staniszewska, A.D. / Talbot, V. / Underwood, E. / Varnes, G.J. / Zhang, A. / Zheng, X. / Johannes, J.W.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Not funded United Kingdom
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over ...Title: Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs.
Authors: Johannes, J.W. / Balazs, A. / Barratt, D. / Bista, M. / Chuba, M.D. / Cosulich, S. / Critchlow, S.E. / Degorce, S.L. / Di Fruscia, P. / Edmondson, S.D. / Embrey, K. / Fawell, S. / Ghosh, A. ...Authors: Johannes, J.W. / Balazs, A. / Barratt, D. / Bista, M. / Chuba, M.D. / Cosulich, S. / Critchlow, S.E. / Degorce, S.L. / Di Fruscia, P. / Edmondson, S.D. / Embrey, K. / Fawell, S. / Ghosh, A. / Gill, S.J. / Gunnarsson, A. / Hande, S.M. / Heightman, T.D. / Hemsley, P. / Illuzzi, G. / Lane, J. / Larner, C. / Leo, E. / Liu, L. / Madin, A. / Martin, S. / McWilliams, L. / O'Connor, M.J. / Orme, J.P. / Pachl, F. / Packer, M.J. / Pei, X. / Pike, A. / Schimpl, M. / She, H. / Staniszewska, A.D. / Talbot, V. / Underwood, E. / Varnes, J.G. / Xue, L. / Yao, T. / Zhang, K. / Zhang, A.X. / Zheng, X.
History
DepositionMay 25, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 15, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / diffrn_source / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _diffrn_source.pdbx_synchrotron_site
Revision 1.2Oct 27, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / diffrn_source / pdbx_initial_refinement_model
Item: _diffrn_source.pdbx_synchrotron_site

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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)79,6296
Polymers78,6262
Non-polymers1,0034
Water8,431468
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8143
Polymers39,3131
Non-polymers5022
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8143
Polymers39,3131
Non-polymers5022
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.573, 92.621, 164.312
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 / DNA ADP-ribosyltransferase PARP1 ...PARP-1 / ADP-ribosyltransferase diphtheria toxin-like 1 / ARTD1 / DNA ADP-ribosyltransferase PARP1 / NAD(+) ADP-ribosyltransferase 1 / ADPRT 1 / Poly[ADP-ribose] synthase 1 / Protein poly-ADP-ribosyltransferase PARP1


Mass: 39312.934 Da / Num. of mol.: 2 / Fragment: catalytic domain (662-1101) / Mutation: V762A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL / Plasmid: pET24a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 Gold (DE3)
References: UniProt: P09874, NAD+ ADP-ribosyltransferase, Transferases; Glycosyltransferases; Pentosyltransferases
#2: Chemical ChemComp-VKQ / 5-[4-[(3-ethyl-2-oxidanylidene-1~{H}-quinolin-7-yl)methyl]piperazin-1-yl]-~{N}-methyl-pyridine-2-carboxamide


Mass: 405.493 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H27N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 468 / 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: 2.35 Å3/Da / Density % sol: 47.67 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 9.5 / Details: 2.5 M ammonium sulfate, 0.1 M Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.85→82.16 Å / Num. obs: 50296 / % possible obs: 93.3 % / Redundancy: 6.5 % / Biso Wilson estimate: 27.2 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.143 / Net I/σ(I): 9.2
Reflection shellResolution: 1.85→1.989 Å / Rmerge(I) obs: 1.354 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 2516 / CC1/2: 0.482

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (24-FEB-2021)refinement
XDSdata reduction
PDB_EXTRACT3.25data extraction
STARANISOdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 1.853→82.16 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.921 / SU R Cruickshank DPI: 0.204 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.216 / SU Rfree Blow DPI: 0.172 / SU Rfree Cruickshank DPI: 0.169
RfactorNum. reflection% reflectionSelection details
Rfree0.2438 2471 4.91 %RANDOM
Rwork0.2131 ---
obs0.2146 50296 78.7 %-
Displacement parametersBiso max: 81.87 Å2 / Biso mean: 33.37 Å2 / Biso min: 11.87 Å2
Baniso -1Baniso -2Baniso -3
1-3.187 Å20 Å20 Å2
2---0.1385 Å20 Å2
3----3.0485 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 1.853→82.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5468 0 70 468 6006
Biso mean--24.2 36.73 -
Num. residues----700
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2021SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes939HARMONIC5
X-RAY DIFFRACTIONt_it5646HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion732SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4880SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5646HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg7631HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3.33
X-RAY DIFFRACTIONt_other_torsion16.46
LS refinement shellResolution: 1.853→1.94 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2667 37 3.68 %
Rwork0.308 969 -
obs--12.34 %
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)
10.57520.0535-0.02370.3561-0.16840.3916-0.0519-0.00290.0299-0.01690.01930.00310.0235-0.01450.03260.0150.0247-0.0291-0.0173-0.0199-0.06329.585443.37715.0709
20.369-0.08590.42180.3319-0.73643.27580.0093-0.0526-0.10210.00770.1412-0.0255-0.0375-0.1712-0.1504-0.01760.0343-0.0149-0.030.0306-0.106430.677526.23438.1256
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A662 - 1011
2X-RAY DIFFRACTION2{ B|* }B662 - 1011

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