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- PDB-8rdz: Crystal Structure of Human ADP-ribose Pyrophosphatase NUDT5 In co... -

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Basic information

Entry
Database: PDB / ID: 8rdz
TitleCrystal Structure of Human ADP-ribose Pyrophosphatase NUDT5 In complex with Ibrutinib
ComponentsADP-sugar pyrophosphatase
KeywordsHYDROLASE / Nudix domain / ADPR / ADP-ribose pyrophosphatase / NUDt5
Function / homology
Function and homology information


ADP-D-ribose pyrophosphorylase / ribonucleoside diphosphate catabolic process / 8-oxo-dGDP phosphatase / nucleobase-containing small molecule metabolic process / ADP-sugar diphosphatase activity / ADP-ribose diphosphatase / D-ribose catabolic process / ADP-ribose diphosphatase activity / nucleoside phosphate metabolic process / 8-oxo-dGDP phosphatase activity ...ADP-D-ribose pyrophosphorylase / ribonucleoside diphosphate catabolic process / 8-oxo-dGDP phosphatase / nucleobase-containing small molecule metabolic process / ADP-sugar diphosphatase activity / ADP-ribose diphosphatase / D-ribose catabolic process / ADP-ribose diphosphatase activity / nucleoside phosphate metabolic process / 8-oxo-dGDP phosphatase activity / ribose phosphate metabolic process / Phosphate bond hydrolysis by NUDT proteins / ATP generation from poly-ADP-D-ribose / nucleotide metabolic process / snoRNA binding / nucleotidyltransferase activity / chromatin remodeling / magnesium ion binding / protein homodimerization activity / extracellular exosome / identical protein binding / nucleus / cytosol
Similarity search - Function
NUDIX hydrolase / NUDIX hydrolase, conserved site / Nudix box signature. / NUDIX domain / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily
Similarity search - Domain/homology
: / ADP-sugar pyrophosphatase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.02 Å
AuthorsRaux, B. / Huber, K.V.M.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Innovative Medicines Initiative875510 Switzerland
CitationJournal: J.Med.Chem. / Year: 2024
Title: Unexpected Noncovalent Off-Target Activity of Clinical BTK Inhibitors Leads to Discovery of a Dual NUDT5/14 Antagonist.
Authors: Balikci, E. / Marques, A.M.C. / Bauer, L.G. / Seupel, R. / Bennett, J. / Raux, B. / Buchan, K. / Simelis, K. / Singh, U. / Rogers, C. / Ward, J. / Cheng, C. / Szommer, T. / Schutzenhofer, K. ...Authors: Balikci, E. / Marques, A.M.C. / Bauer, L.G. / Seupel, R. / Bennett, J. / Raux, B. / Buchan, K. / Simelis, K. / Singh, U. / Rogers, C. / Ward, J. / Cheng, C. / Szommer, T. / Schutzenhofer, K. / Elkins, J.M. / Sloman, D.L. / Ahel, I. / Fedorov, O. / Brennan, P.E. / Huber, K.V.M.
History
DepositionDec 9, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ADP-sugar pyrophosphatase
B: ADP-sugar pyrophosphatase
C: ADP-sugar pyrophosphatase
D: ADP-sugar pyrophosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,81323
Polymers97,4224
Non-polymers2,39119
Water2,144119
1
A: ADP-sugar pyrophosphatase
C: ADP-sugar pyrophosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,81410
Polymers48,7112
Non-polymers1,1028
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7400 Å2
ΔGint-81 kcal/mol
Surface area16430 Å2
MethodPISA
2
B: ADP-sugar pyrophosphatase
D: ADP-sugar pyrophosphatase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,00013
Polymers48,7112
Non-polymers1,28911
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8270 Å2
ΔGint-71 kcal/mol
Surface area16210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.710, 59.200, 79.431
Angle α, β, γ (deg.)80.652, 82.958, 77.028
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
ADP-sugar pyrophosphatase / 8-oxo-dGDP phosphatase / Nuclear ATP-synthesis protein NUDIX5 / Nucleoside diphosphate-linked ...8-oxo-dGDP phosphatase / Nuclear ATP-synthesis protein NUDIX5 / Nucleoside diphosphate-linked moiety X motif 5 / Nudix motif 5 / hNUDT5 / YSA1H


Mass: 24355.596 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT5, NUDIX5, HSPC115 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9UKK9, ADP-ribose diphosphatase, 8-oxo-dGDP phosphatase, ADP-D-ribose pyrophosphorylase
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-A1H14 / Ibrutinib (unbound form) / 1-[(3S)-3-[4-azanyl-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one


Mass: 440.497 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H24N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / 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: 2.55 Å3/Da / Density % sol: 51.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: Tris, PEG4K, magnesium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 8, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.02→49.56 Å / Num. obs: 53078 / % possible obs: 96.87 % / Redundancy: 2.8 % / CC1/2: 0.994 / CC star: 0.998 / Rmerge(I) obs: 0.05739 / Rpim(I) all: 0.04047 / Rrim(I) all: 0.07063 / Net I/σ(I): 7.35
Reflection shellResolution: 2.02→2.092 Å / Rmerge(I) obs: 0.8753 / Num. unique obs: 5256 / CC1/2: 0.243 / CC star: 0.625

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
PHASERphasing
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.02→49.557 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.917 / SU B: 7.612 / SU ML: 0.196 / Cross valid method: FREE R-VALUE / ESU R: 0.226 / ESU R Free: 0.211
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.289 2657 5.02 %
Rwork0.2207 50268 -
all0.224 --
obs-52925 96.943 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 45.269 Å2
Baniso -1Baniso -2Baniso -3
1-2.076 Å21.454 Å22.016 Å2
2---0.918 Å21.351 Å2
3---0.306 Å2
Refinement stepCycle: LAST / Resolution: 2.02→49.557 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5894 0 168 119 6181
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0126184
X-RAY DIFFRACTIONr_bond_other_d0.0010.0165888
X-RAY DIFFRACTIONr_angle_refined_deg1.7731.8568396
X-RAY DIFFRACTIONr_angle_other_deg0.5841.76113637
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.8785755
X-RAY DIFFRACTIONr_dihedral_angle_2_deg24.9347.70374
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg1.89108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.436101042
X-RAY DIFFRACTIONr_dihedral_angle_6_deg13.67710257
X-RAY DIFFRACTIONr_chiral_restr0.0880.2955
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.027118
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021258
X-RAY DIFFRACTIONr_nbd_refined0.220.21177
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1970.25345
X-RAY DIFFRACTIONr_nbtor_refined0.180.22907
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0840.23269
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.2204
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.050.21
X-RAY DIFFRACTIONr_metal_ion_refined0.120.28
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1830.28
X-RAY DIFFRACTIONr_nbd_other0.1730.243
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0610.22
X-RAY DIFFRACTIONr_mcbond_it4.6034.3583038
X-RAY DIFFRACTIONr_mcbond_other4.6014.3583038
X-RAY DIFFRACTIONr_mcangle_it6.4727.8063784
X-RAY DIFFRACTIONr_mcangle_other6.4717.8073785
X-RAY DIFFRACTIONr_scbond_it4.8374.9273146
X-RAY DIFFRACTIONr_scbond_other4.8364.9283147
X-RAY DIFFRACTIONr_scangle_it7.1078.8334611
X-RAY DIFFRACTIONr_scangle_other7.1068.8334612
X-RAY DIFFRACTIONr_lrange_it9.3141.7056509
X-RAY DIFFRACTIONr_lrange_other9.31241.7316493
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.02-2.0720.3862000.35236660.35440210.8870.89496.14520.346
2.072-2.1290.3431710.32236100.32339390.9240.92395.98880.313
2.129-2.1910.3881840.30535030.30938450.9020.92995.89080.299
2.191-2.2580.3471830.32333830.32437040.8020.88996.27430.311
2.258-2.3320.3211800.26632970.26936060.9360.95696.42260.251
2.332-2.4140.3261710.25732020.2634790.9330.95996.95310.24
2.414-2.5040.3271590.24531060.24933630.9310.96397.08590.226
2.504-2.6060.3241780.23429260.23932000.9420.967970.216
2.606-2.7220.3711390.2628870.26531080.9230.96297.36160.243
2.722-2.8540.3221530.23127230.23629680.9360.97196.90030.214
2.854-3.0080.2991430.23525880.23928230.9470.96896.74110.223
3.008-3.190.2941340.2124710.21426810.9420.97497.16520.202
3.19-3.4090.2581130.2323290.23124930.9580.9797.95430.225
3.409-3.6810.2621100.20621770.20923390.9670.97897.77680.207
3.681-4.030.2521250.19619710.19921490.960.97997.53370.203
4.03-4.5020.29960.17317800.17819360.9540.98396.90080.188
4.502-5.1910.254720.17116030.17517210.970.98597.32710.191
5.191-6.3410.297600.19913630.20314430.9690.98298.6140.215
6.341-8.8940.194500.17510810.17611350.9810.98299.64760.195
8.894-49.5570.255360.2126020.2156390.9630.97799.84350.228

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