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- PDB-5xsu: novel orally efficacious inhibitors complexed with PARP1 -

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Basic information

Entry
Database: PDB / ID: 5xsu
Titlenovel orally efficacious inhibitors complexed with PARP1
ComponentsPoly [ADP-ribose] polymerase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / complex structure / 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 / 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. / 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-8E3 / Poly [ADP-ribose] polymerase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.4 Å
AuthorsLiu, Q. / Xu, Y.
CitationJournal: Eur J Med Chem / Year: 2018
Title: Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors
Authors: Chen, X. / Huan, X. / Liu, Q. / Wang, Y. / He, Q. / Tan, C. / Chen, Y. / Ding, J. / Xu, Y. / Miao, Z. / Yang, C.
History
DepositionJun 15, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 25, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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)161,05924
Polymers158,3214
Non-polymers2,73820
Water2,954164
1
A: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,4578
Polymers39,5801
Non-polymers8777
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,4578
Polymers39,5801
Non-polymers8777
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0734
Polymers39,5801
Non-polymers4923
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Poly [ADP-ribose] polymerase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0734
Polymers39,5801
Non-polymers4923
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.670, 107.270, 142.540
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and ((resid 4 and (name N or name...
21(chain B and ((resid 4 and (name N or name...
31(chain C and ((resid 4 and (name N or name...
41(chain D and (resid 4 through 49 or (resid 50...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LEULEULEULEU(chain A and ((resid 4 and (name N or name...AA49
12LYSLYSLYSLYS(chain A and ((resid 4 and (name N or name...AA1 - 3496 - 354
13LYSLYSLYSLYS(chain A and ((resid 4 and (name N or name...AA1 - 3496 - 354
14LYSLYSLYSLYS(chain A and ((resid 4 and (name N or name...AA1 - 3496 - 354
15LYSLYSLYSLYS(chain A and ((resid 4 and (name N or name...AA1 - 3496 - 354
21LEULEULEULEU(chain B and ((resid 4 and (name N or name...BB49
22LYSLYSLYSLYS(chain B and ((resid 4 and (name N or name...BB1 - 3496 - 354
23LYSLYSLYSLYS(chain B and ((resid 4 and (name N or name...BB1 - 3496 - 354
24LYSLYSLYSLYS(chain B and ((resid 4 and (name N or name...BB1 - 3496 - 354
25LYSLYSLYSLYS(chain B and ((resid 4 and (name N or name...BB1 - 3496 - 354
31LEULEULEULEU(chain C and ((resid 4 and (name N or name...CC49
32LYSLYSTHRTHR(chain C and ((resid 4 and (name N or name...CC1 - 3506 - 355
33LYSLYSTHRTHR(chain C and ((resid 4 and (name N or name...CC1 - 3506 - 355
34LYSLYSTHRTHR(chain C and ((resid 4 and (name N or name...CC1 - 3506 - 355
35LYSLYSTHRTHR(chain C and ((resid 4 and (name N or name...CC1 - 3506 - 355
41LEULEUTYRTYR(chain D and (resid 4 through 49 or (resid 50...DD4 - 499 - 54
42SERSERSERSER(chain D and (resid 4 through 49 or (resid 50...DD5055
43LEULEUPHEPHE(chain D and (resid 4 through 49 or (resid 50...DD4 - 3489 - 353
44LEULEUPHEPHE(chain D and (resid 4 through 49 or (resid 50...DD4 - 3489 - 353
45LEULEUPHEPHE(chain D and (resid 4 through 49 or (resid 50...DD4 - 3489 - 353
46LEULEUPHEPHE(chain D and (resid 4 through 49 or (resid 50...DD4 - 3489 - 353

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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: 39580.262 Da / Num. of mol.: 4 / Fragment: UNP residues 660-1011
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP1, ADPRT, PPOL / Plasmid: pGEX-6P-1 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2 / References: UniProt: P09874, NAD+ ADP-ribosyltransferase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-8E3 / 6-fluoranyl-2-(4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-yl)-1~{H}-benzimidazole-4-carboxamide


Mass: 300.288 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H13FN4O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / 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: 2.5 Å3/Da / Density % sol: 50.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.1M Tris pH 7.5, 1% PEG400, 2.1M (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 14, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.4→48.714 Å / Num. obs: 120032 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 3.859 % / Biso Wilson estimate: 40.42 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.072 / Rrim(I) all: 0.084 / Χ2: 0.981 / Net I/σ(I): 13.6 / Num. measured all: 463165 / Scaling rejects: 23
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.4-2.463.8620.532.8334312888788850.7750.617100
2.46-2.533.8660.4583.2433459865786550.8250.533100
2.53-2.63.8640.3843.8432551842884250.8730.446100
2.6-2.683.870.3234.4831689818981880.9160.376100
2.68-2.773.8740.2695.3130567789278910.9310.312100
2.77-2.873.8710.2116.6429823770477040.9580.245100
2.87-2.983.8710.1757.9128749742774260.9680.203100
2.98-3.13.8690.13110.0627365707370730.9820.153100
3.1-3.243.8680.10112.5726461684168410.9880.117100
3.24-3.393.8660.07715.6325158650865080.9930.09100
3.39-3.583.8640.06318.5424043622462230.9950.073100
3.58-3.793.8430.05221.5422468584658460.9960.061100
3.79-4.063.8230.04823.4621056550855080.9970.056100
4.06-4.383.7930.04326.5319553515651550.9970.05100
4.38-4.83.6750.03928.0617354472947220.9970.04699.9
4.8-5.373.9190.03929.3716759427642760.9980.045100
5.37-6.23.9380.04128.3714804376037590.9970.047100
6.2-7.593.9330.03830.0812435316231620.9980.044100
7.59-10.733.890.03434.639577246324620.9980.039100
10.73-48.7143.7660.03435.194982134513230.9980.0498.4

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.09 Å48.71 Å
Translation6.09 Å48.71 Å

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Processing

Software
NameVersionClassification
PHENIXrefinement
XSCALEdata scaling
PHASER2.7.16model building
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HHY

4hhy


Resolution: 2.4→48.714 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.15 / Phase error: 28.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2741 3598 3 %
Rwork0.2211 116420 -
obs0.2227 120018 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 136.41 Å2 / Biso mean: 45.8354 Å2 / Biso min: 14.73 Å2
Refinement stepCycle: final / Resolution: 2.4→48.714 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9562 0 168 164 9894
Biso mean--46.61 36.84 -
Num. residues----1338
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0089904
X-RAY DIFFRACTIONf_angle_d1.01713506
X-RAY DIFFRACTIONf_chiral_restr0.0581566
X-RAY DIFFRACTIONf_plane_restr0.0071723
X-RAY DIFFRACTIONf_dihedral_angle_d6.3715842
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5006X-RAY DIFFRACTION10.352TORSIONAL
12B5006X-RAY DIFFRACTION10.352TORSIONAL
13C5006X-RAY DIFFRACTION10.352TORSIONAL
14D5006X-RAY DIFFRACTION10.352TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 26 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.4-2.43160.35661390.275744524591
2.4316-2.46490.30811390.268944734612
2.4649-2.50010.30581400.267344884628
2.5001-2.53740.36571430.263944964639
2.5374-2.57710.35021370.255544644601
2.5771-2.61930.30811380.257145144652
2.6193-2.66450.29391330.248944544587
2.6645-2.71290.35431380.26445104648
2.7129-2.76510.32441390.267444324571
2.7651-2.82150.36941380.254345094647
2.8215-2.88290.27031410.257444694610
2.8829-2.94990.27831360.253244744610
2.9499-3.02370.3821360.256244574593
3.0237-3.10540.3061390.259344984637
3.1054-3.19680.33811420.255744634605
3.1968-3.29990.3381400.25244954635
3.2999-3.41790.31141370.241144634600
3.4179-3.55470.23771400.218245284668
3.5547-3.71640.26591370.214544634600
3.7164-3.91220.22471390.191244734612
3.9122-4.15720.25011360.184944804616
4.1572-4.4780.17591400.170444964636
4.478-4.92830.2331350.176644444579
4.9283-5.64050.24331380.200644844622
5.6405-7.10290.32171360.241244874623
7.1029-48.7240.22721420.193844544596

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