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- PDB-8otv: Crystal structure of NUDT14 complexed with novel compound -

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Basic information

Entry
Database: PDB / ID: 8otv
TitleCrystal structure of NUDT14 complexed with novel compound
ComponentsUridine diphosphate glucose pyrophosphatase NUDT14
KeywordsHYDROLASE / HYDROLASE INHIBITOR / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


Synthesis of dolichyl-phosphate-glucose / UDP-sugar diphosphatase / UDP-sugar diphosphatase activity / nucleoside phosphate metabolic process / ribose phosphate metabolic process / ADP-ribose diphosphatase activity / protein N-linked glycosylation via asparagine / identical protein binding / metal ion binding / cytosol
Similarity search - Function
Nucleoside diphosphate pyrophosphatase / Nudix hydrolase domain profile. / NUDIX hydrolase domain / NUDIX hydrolase-like domain superfamily
Similarity search - Domain/homology
: / Uridine diphosphate glucose pyrophosphatase NUDT14
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsBalikci, E. / Feyerherm, C. / Bradshaw, W. / Seupel, R. / Brennan, P.E. / Bountra, C. / von Delft, F. / Huber, K. / Structural Genomics Consortium (SGC)
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
DepositionApr 21, 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: Uridine diphosphate glucose pyrophosphatase NUDT14
B: Uridine diphosphate glucose pyrophosphatase NUDT14
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,3606
Polymers48,4572
Non-polymers9034
Water3,891216
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7320 Å2
ΔGint-44 kcal/mol
Surface area18820 Å2
Unit cell
Length a, b, c (Å)51.250, 90.967, 108.099
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Uridine diphosphate glucose pyrophosphatase NUDT14 / UDPG pyrophosphatase / UGPPase / Nucleoside diphosphate-linked moiety X motif 14 / Nudix motif 14


Mass: 24228.287 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: CN(CC1)CCC1N2C3=NC=NC(N)=C3C(C4=CC=C(OC5=CC=CC=C5)C=C4)=N2
Source: (gene. exp.) Homo sapiens (human) / Gene: NUDT14, UGPP / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O95848, UDP-sugar diphosphatase
#2: Chemical ChemComp-W0O / 1-(1-methylpiperidin-4-yl)-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 400.476 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 216 / 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: 2.6 Å3/Da / Density % sol: 52.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.2 M sodium chloride, 25% PEG3350, 0.1M Bis-Tris pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jul 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.82→54.05 Å / Num. obs: 556903 / % possible obs: 99.5 % / Redundancy: 6.4 % / Biso Wilson estimate: 36.09 Å2 / CC1/2: 0.999 / Net I/σ(I): 9.6
Reflection shellResolution: 1.82→1.85 Å / Num. unique obs: 17936 / CC1/2: 0.295

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
DIALSdata reduction
Aimlessdata scaling
Aimlessphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.82→54.05 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2396 1974 4.36 %
Rwork0.2061 --
obs0.2075 45224 98.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.82→54.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3212 0 65 216 3493
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043358
X-RAY DIFFRACTIONf_angle_d0.7484572
X-RAY DIFFRACTIONf_dihedral_angle_d6.865519
X-RAY DIFFRACTIONf_chiral_restr0.047504
X-RAY DIFFRACTIONf_plane_restr0.006589
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.82-1.870.42231120.43042385X-RAY DIFFRACTION77
1.87-1.920.42411340.38512967X-RAY DIFFRACTION96
1.92-1.970.35971430.33243115X-RAY DIFFRACTION100
1.97-2.040.27041410.28943100X-RAY DIFFRACTION100
2.04-2.110.32091420.26033122X-RAY DIFFRACTION100
2.11-2.190.25931420.25983091X-RAY DIFFRACTION100
2.19-2.290.2411420.22053131X-RAY DIFFRACTION100
2.29-2.410.25161430.21133132X-RAY DIFFRACTION100
2.41-2.560.24781440.2213146X-RAY DIFFRACTION100
2.56-2.760.25541430.22463141X-RAY DIFFRACTION100
2.76-3.040.26141440.22563160X-RAY DIFFRACTION100
3.04-3.480.23281450.23180X-RAY DIFFRACTION100
3.48-4.390.21421460.16673214X-RAY DIFFRACTION100
4.39-54.050.19851530.16853366X-RAY DIFFRACTION100
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)
16.7647-3.6685-1.81514.87971.34892.71220.01430.03860.27610.1167-0.03550.0876-0.04850.17250.04050.2427-0.0425-0.03260.23330.00290.2379-4.247118.8056-15.3149
23.4270.99561.46733.5981.89532.18220.0059-0.0718-0.11090.31760.0549-0.29160.32680.1763-0.07490.33560.0510.00390.28670.03690.1876-2.1891-2.2225-21.5896
34.73242.6682-3.52693.3353-0.16134.78010.37680.53950.69170.58470.8668-0.21450.04812.0863-1.20090.6746-0.0063-0.1640.6465-0.10560.631912.163314.6703-7.6102
45.09320.50522.94293.07451.62823.1866-0.09650.14380.3423-0.00930.0732-0.50950.06060.48390.01750.24570.06220.00450.3983-0.01990.34313.74866.2477-21.2751
51.8971-0.4711-0.9212.98580.84572.9417-0.03920.0796-0.12510.09530.0133-0.03460.2770.08770.02630.27770.0495-0.03960.2692-0.01120.2064-10.4526-5.4687-25.9757
61.08840.59910.04291.3033-0.30581.06480.07580.0270.10230.1002-0.00950.0603-0.15720.0887-0.06370.29820.0028-0.02380.2595-0.02290.2529-9.745612.8103-12.6869
71.7358-0.09970.11751.6256-0.351.8856-0.095-0.03460.14390.14370.0486-0.0637-0.18720.24420.04810.3678-0.0356-0.03440.2994-0.01230.2576-12.96519.6559-6.437
84.6571-1.1818-0.57132.270.4944.24350.09070.1431-0.303-0.0367-0.15290.2976-0.1623-0.40080.06490.36320.0255-0.02750.2333-0.0350.261-22.2923-0.5143-5.8318
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid 1 through 38 )
2X-RAY DIFFRACTION2chain 'B' and (resid 39 through 73 )
3X-RAY DIFFRACTION3chain 'B' and (resid 74 through 83 )
4X-RAY DIFFRACTION4chain 'B' and (resid 84 through 114 )
5X-RAY DIFFRACTION5chain 'B' and (resid 115 through 220 )
6X-RAY DIFFRACTION6chain 'A' and (resid 1 through 73 )
7X-RAY DIFFRACTION7chain 'A' and (resid 74 through 150 )
8X-RAY DIFFRACTION8chain 'A' and (resid 151 through 219 )

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