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- PDB-8c8c: Crystal Structure of Phosphatidylinositol 5-phosphate 4-kinase ty... -

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Basic information

Entry
Database: PDB / ID: 8c8c
TitleCrystal Structure of Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PI5P4Ka) bound to an inhibitor
ComponentsPhosphatidylinositol 5-phosphate 4-kinase type-2 alpha
KeywordsTRANSFERASE / Inhibitor / ATP
Function / homology
Function and homology information


vesicle-mediated cholesterol transport / 1-phosphatidylinositol-5-phosphate 4-kinase / 1-phosphatidylinositol-5-phosphate 4-kinase activity / 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate biosynthetic process / Synthesis of PIPs in the nucleus / 1-phosphatidylinositol-4-phosphate 5-kinase activity / autophagosome-lysosome fusion / positive regulation of autophagosome assembly / megakaryocyte development / PI5P Regulates TP53 Acetylation ...vesicle-mediated cholesterol transport / 1-phosphatidylinositol-5-phosphate 4-kinase / 1-phosphatidylinositol-5-phosphate 4-kinase activity / 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate biosynthetic process / Synthesis of PIPs in the nucleus / 1-phosphatidylinositol-4-phosphate 5-kinase activity / autophagosome-lysosome fusion / positive regulation of autophagosome assembly / megakaryocyte development / PI5P Regulates TP53 Acetylation / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / photoreceptor outer segment / autophagosome / negative regulation of insulin receptor signaling pathway / photoreceptor inner segment / regulation of autophagy / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / lysosome / phosphorylation / protein homodimerization activity / nucleoplasm / ATP binding / plasma membrane / cytosol
Similarity search - Function
Phosphatidylinositol-4-phosphate 5-kinase / : / Phosphatidylinositol-4-phosphate 5-kinase, core / Phosphatidylinositol-4-phosphate 5-kinase, N-terminal / Phosphatidylinositol-4-phosphate 5-Kinase / Phosphatidylinositol phosphate kinase (PIPK) domain profile. / Phosphatidylinositol phosphate kinases
Similarity search - Domain/homology
Chem-U1U / Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.096 Å
AuthorsHarborne, S.P.D. / Howard, T.D. / Ogg, D.T.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Other private United Kingdom
CitationJournal: Rsc Med Chem / Year: 2023
Title: Identification of ARUK2002821 as an isoform-selective PI5P4K alpha inhibitor.
Authors: Willems, H.M.G. / Edwards, S. / Boffey, H.K. / Chawner, S.J. / Green, C. / Romero, T. / Winpenny, D. / Skidmore, J. / Clarke, J.H. / Andrews, S.P.
History
DepositionJan 19, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2382
Polymers42,8591
Non-polymers3791
Water2,252125
1
A: Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha
hetero molecules

A: Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,4764
Polymers85,7192
Non-polymers7582
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_655-x+1,y,-z+1/21
Buried area2320 Å2
ΔGint-12 kcal/mol
Surface area28290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.661, 84.935, 128.346
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha / 1-phosphatidylinositol 5-phosphate 4-kinase 2-alpha / Diphosphoinositide kinase 2-alpha / PIP5KIII ...1-phosphatidylinositol 5-phosphate 4-kinase 2-alpha / Diphosphoinositide kinase 2-alpha / PIP5KIII / Phosphatidylinositol 5-Phosphate 4-Kinase / PI5P4Kalpha / Phosphatidylinositol 5-phosphate 4-kinase type II alpha / PI(5)P 4-kinase type II alpha / PIP4KII-alpha / PtdIns(4)P-5-kinase B isoform / PtdIns(4)P-5-kinase C isoform / PtdIns(5)P-4-kinase isoform 2-alpha


Mass: 42859.383 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIP4K2A, PI5P4KA, PIP5K2, PIP5K2A / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P48426, 1-phosphatidylinositol-5-phosphate 4-kinase
#2: Chemical ChemComp-U1U / ~{N}-(3-chloranyl-4-methoxy-phenyl)-7-(3,4-dimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 378.855 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19ClN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.28 Å3/Da / Density % sol: 46.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 24 % PEG smear low 0.04 M CaCl 0.04 M NaFormate 0.1 M Tris pH pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.096→42.504 Å / Num. obs: 19434 / % possible obs: 84.7 % / Redundancy: 1.9 % / Biso Wilson estimate: 38.071 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.04 / Rpim(I) all: 0.04 / Rrim(I) all: 0.056 / Χ2: 0.89 / Net I/σ(I): 10.3
Reflection shellResolution: 2.1→2.16 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.532 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 368 / CC1/2: 0.766 / Rpim(I) all: 0.532 / Rrim(I) all: 0.753 / Χ2: 0.92 / % possible all: 19.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0403refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.096→42.504 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.918 / SU B: 17.823 / SU ML: 0.216 / Cross valid method: FREE R-VALUE / ESU R: 0.275 / ESU R Free: 0.238
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2819 961 4.948 %
Rwork0.2165 18461 -
all0.22 --
obs-19422 84.206 %
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: 51.147 Å2
Baniso -1Baniso -2Baniso -3
1-0.964 Å2-0 Å20 Å2
2---0.161 Å2-0 Å2
3----0.803 Å2
Refinement stepCycle: LAST / Resolution: 2.096→42.504 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2420 0 27 125 2572
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0122516
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162352
X-RAY DIFFRACTIONr_angle_refined_deg1.4611.6543404
X-RAY DIFFRACTIONr_angle_other_deg0.4871.5835406
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9265294
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.4625.38513
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.45210435
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.91210124
X-RAY DIFFRACTIONr_chiral_restr0.0650.2369
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022888
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02584
X-RAY DIFFRACTIONr_nbd_refined0.2180.2545
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1940.22169
X-RAY DIFFRACTIONr_nbtor_refined0.1890.21257
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.21347
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1880.2107
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.040.23
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0940.214
X-RAY DIFFRACTIONr_nbd_other0.1340.267
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.150.23
X-RAY DIFFRACTIONr_mcbond_it3.4063.9421188
X-RAY DIFFRACTIONr_mcbond_other3.4063.9431188
X-RAY DIFFRACTIONr_mcangle_it4.8487.0571478
X-RAY DIFFRACTIONr_mcangle_other4.8477.0561479
X-RAY DIFFRACTIONr_scbond_it4.0524.221328
X-RAY DIFFRACTIONr_scbond_other4.0514.2191328
X-RAY DIFFRACTIONr_scangle_it6.0327.6071926
X-RAY DIFFRACTIONr_scangle_other6.037.6061927
X-RAY DIFFRACTIONr_lrange_it7.69438.192900
X-RAY DIFFRACTIONr_lrange_other7.68137.7052884
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
2.096-2.150.349150.3713030.36916690.9290.89219.05330.372
2.15-2.2090.326340.3535890.35216450.9070.90637.87230.356
2.209-2.2730.458480.4799690.47915850.9130.86564.1640.508
2.273-2.3430.401580.31411800.31815410.8980.93480.33740.307
2.343-2.4190.322870.28113390.28415220.9190.94893.69250.27
2.419-2.5040.283550.24513820.24714490.9470.96299.17180.228
2.504-2.5980.29480.23213430.23413940.9360.96299.78480.213
2.598-2.7041.168551.04110571.04813500.8190.85682.37041.079
2.704-2.8230.306620.29312310.29313070.930.94798.92880.274
2.823-2.9610.399580.21211780.2212420.9140.97399.51690.2
2.961-3.120.236520.20111420.20211960.9590.97899.83280.197
3.12-3.3080.254630.20810550.21111190.9670.97899.91060.208
3.308-3.5350.29680.1979950.20310670.9430.98299.62510.201
3.535-3.8160.218520.179320.1739870.9670.98599.6960.181
3.816-4.1770.28420.1548830.169260.9590.98799.8920.168
4.177-4.6640.237420.1458020.1498450.9710.98799.88170.169
4.664-5.3750.222370.167030.1647410.9630.98499.86510.187
5.375-6.5570.298470.2365920.2416400.9510.97599.84380.272
6.557-9.1640.205240.2054900.2055150.9750.97799.80580.246
9.164-42.5040.226140.2192960.2193150.9570.9798.41270.261
Refinement TLS params.Method: refined / Origin x: 14.2046 Å / Origin y: 20.8038 Å / Origin z: 15.8287 Å
111213212223313233
T0.0183 Å20.0111 Å20.0216 Å2-0.0529 Å2-0.023 Å2--0.0944 Å2
L2.4502 °2-0.5396 °21.3814 °2-0.7699 °2-0.5949 °2--2.3938 °2
S-0.0614 Å °-0.2362 Å °0.0423 Å °0.1177 Å °0.0872 Å °0.1432 Å °-0.07 Å °-0.3093 Å °-0.0258 Å °
Refinement TLS groupSelection: ALL

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