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- PDB-8bq4: Crystal Structure of Phosphatidylinositol 5-Phosphate 4-Kinase (P... -

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Basic information

Entry
Database: PDB / ID: 8bq4
TitleCrystal Structure of Phosphatidylinositol 5-Phosphate 4-Kinase (PI5P4K2C) bound to an inhibitor
ComponentsPhosphatidylinositol 5-phosphate 4-kinase type-2 gamma
KeywordsTRANSFERASE / LIPID KINASE / ATP-COMPETITIVE INHIBITOR / PHOSPHATIDYLINOSITOL 5-PHOSPHATE
Function / homology
Function and homology information


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 / intracellular organelle / positive regulation of autophagosome assembly / PI5P Regulates TP53 Acetylation / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process ...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 / intracellular organelle / positive regulation of autophagosome assembly / PI5P Regulates TP53 Acetylation / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / negative regulation of insulin receptor signaling pathway / autophagosome / regulation of autophagy / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / endoplasmic reticulum / extracellular exosome / nucleoplasm / ATP binding / identical protein 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-QZR / Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.42 Å
AuthorsOgg, D.J. / Howard, T.D.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Alzheimers Research UK (ARUK)ARUK-2015DDI-CAM United Kingdom
CitationJournal: J.Med.Chem. / Year: 2023
Title: The Identification of Potent, Selective, and Brain Penetrant PI5P4K gamma Inhibitors as In Vivo-Ready Tool Molecules.
Authors: Rooney, T.P.C. / Aldred, G.G. / Boffey, H.K. / Willems, H.M.G. / Edwards, S. / Chawner, S.J. / Scott, D.E. / Green, C. / Winpenny, D. / Skidmore, J. / Clarke, J.H. / Andrews, S.P.
History
DepositionNov 18, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jul 19, 2023Group: Data collection / Database references ...Data collection / Database references / Source and taxonomy / Structure summary
Category: diffrn_source / entity_name_com ...diffrn_source / entity_name_com / entity_src_gen / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.3Feb 7, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)84,6754
Polymers84,0362
Non-polymers6392
Water68538
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2100 Å2
ΔGint-11 kcal/mol
Surface area28940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.090, 78.860, 96.970
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma / Phosphatidylinositol 5-phosphate 4-kinase type II gamma / PI(5)P 4-kinase type II gamma / PIP4KII-gamma


Mass: 42017.918 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIP4K2C, PIP5K2C / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q8TBX8, 1-phosphatidylinositol-5-phosphate 4-kinase
#2: Chemical ChemComp-QZR / 6-methyl-~{N}-(4-methylsulfonylphenyl)thieno[2,3-d]pyrimidin-4-amine


Mass: 319.402 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H13N3O2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / 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: 2.73 Å3/Da / Density % sol: 54.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 20% w/v Peg3350, 0.3 M Ammonium Tartrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97624 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 3, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97624 Å / Relative weight: 1
ReflectionResolution: 2.42→75.44 Å / Num. obs: 35432 / % possible obs: 98.8 % / Redundancy: 6.4 % / CC1/2: 0.999 / Rrim(I) all: 0.079 / Net I/σ(I): 11.4
Reflection shellResolution: 2.42→2.46 Å / Num. unique obs: 1773 / CC1/2: 0.403

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Processing

Software
NameVersionClassification
REFMAC5.8.0230refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GK9

2gk9


Resolution: 2.42→75.44 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.94 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.247 1752 5 %RANDOM
Rwork0.222 ---
obs0.223 35005 97.7 %-
Displacement parametersBiso mean: 100.01 Å2
Baniso -1Baniso -2Baniso -3
1-12.8256 Å20 Å20 Å2
2---20.2378 Å20 Å2
3---7.4123 Å2
Refinement stepCycle: LAST / Resolution: 2.42→75.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4743 0 42 38 4823
LS refinement shellResolution: 2.42→2.44 Å / Total num. of bins used: 50 /
Rfactor% reflection
Rfree0.271 -
Rwork0.2522 -
obs-99.86 %
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)
11.258-0.0885-0.48850.1260.6033.63420.0023-0.32570.0206-0.0706-0.0584-0.0566-0.0541-0.32750.05610.30440.0053-0.02520.14590.01130.3787-11.900718.484440.602
21.70180.2495-1.14910.0719-0.42683.41120.01460.2006-0.00990.038-0.00140.051-0.07260.2114-0.01320.31450.0031-0.00470.07260.02940.364814.445519.8835-7.0151
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A45 - 501
2X-RAY DIFFRACTION2B45 - 501

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