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- PDB-6ym3: Crystal structure of Compound 1 with PIP4K2A -

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Basic information

Entry
Database: PDB / ID: 6ym3
TitleCrystal structure of Compound 1 with PIP4K2A
ComponentsPhosphatidylinositol 5-phosphate 4-kinase type-2 alpha
KeywordsTRANSFERASE / PIP4K2A
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-OYZ / PHOSPHATE ION / Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsHolton, S.J. / Wortmann, L. / Braeuer, N. / Irlbacher, H. / Weiske, J. / Lechner, C. / Meier, R. / Puetter, V. / Christ, C. / ter Laak, T. ...Holton, S.J. / Wortmann, L. / Braeuer, N. / Irlbacher, H. / Weiske, J. / Lechner, C. / Meier, R. / Puetter, V. / Christ, C. / ter Laak, T. / Lienau, P. / Lesche, R. / Nicke, B. / Bauser, M. / Haegebarth, A. / von Nussbaum, F. / Mumberg, D. / Lemos, C.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A.
Authors: Wortmann, L. / Brauer, N. / Holton, S.J. / Irlbacher, H. / Weiske, J. / Lechner, C. / Meier, R. / Karen, J. / Sioberg, C.B. / Putter, V. / Christ, C.D. / Ter Laak, A. / Lienau, P. / Lesche, ...Authors: Wortmann, L. / Brauer, N. / Holton, S.J. / Irlbacher, H. / Weiske, J. / Lechner, C. / Meier, R. / Karen, J. / Sioberg, C.B. / Putter, V. / Christ, C.D. / Ter Laak, A. / Lienau, P. / Lesche, R. / Nicke, B. / Cheung, S.H. / Bauser, M. / Haegebarth, A. / von Nussbaum, F. / Mumberg, D. / Lemos, C.
History
DepositionApr 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 17, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_2 / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 24, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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


Theoretical massNumber of molelcules
Total (without water)91,6976
Polymers90,6262
Non-polymers1,0714
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3280 Å2
ΔGint-24 kcal/mol
Surface area29590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.934, 98.132, 104.256
Angle α, β, γ (deg.)90.000, 92.960, 90.000
Int Tables number4
Space group name H-MP1211

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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 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: 45312.984 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIP4K2A, PIP5K2, PIP5K2A / Production host: Escherichia coli (E. coli)
References: UniProt: P48426, 1-phosphatidylinositol-5-phosphate 4-kinase
#2: Chemical ChemComp-OYZ / (2~{R})-2-[[3-cyano-2-[4-(2-ethoxyphenyl)phenyl]-5,8-dihydro-1,7-naphthyridin-4-yl]amino]propanoic acid


Mass: 440.494 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H24N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 2.48 Å3/Da / Density % sol: 50.33 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: PEG3350, magnesium formate, glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.05→45.99 Å / Num. obs: 59573 / % possible obs: 99.3 % / Redundancy: 3.68 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 12.5
Reflection shellResolution: 2.05→2.12 Å / Rmerge(I) obs: 0.512 / Num. unique obs: 9014 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2YBX

2ybx


Resolution: 2.05→45.99 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.94 / SU B: 13.248 / SU ML: 0.165 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.174 / ESU R Free: 0.166
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.25 2100 3.8 %RANDOM
Rwork0.2019 ---
obs0.2036 53260 99.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 122.71 Å2 / Biso mean: 42.319 Å2 / Biso min: 18.85 Å2
Baniso -1Baniso -2Baniso -3
1-0.41 Å2-0 Å20.87 Å2
2---2.22 Å2-0 Å2
3---1.71 Å2
Refinement stepCycle: final / Resolution: 2.05→45.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5169 0 76 146 5391
Biso mean--35.14 42.45 -
Num. residues----626
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0135394
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174939
X-RAY DIFFRACTIONr_angle_refined_deg2.1421.6627290
X-RAY DIFFRACTIONr_angle_other_deg1.4441.58611433
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.685623
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.14523.153295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.78815958
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3351526
X-RAY DIFFRACTIONr_chiral_restr0.1040.2675
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.025921
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021109
LS refinement shellResolution: 2.05→2.1 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.341 150 -
Rwork0.332 3815 -
obs--96.14 %
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)
11.26170.0563-0.33311.3402-0.97932.61220.00770.06890.1304-0.1298-0.0343-0.0401-0.0358-0.08630.02670.0295-0.00660.01340.5771-0.03460.02911.014.981-6.111
20.9383-0.0059-0.35560.78490.28063.3023-0.0585-0.1331-0.01470.1494-0.0098-0.05160.0410.0380.06830.0413-0.00640.00190.50820.02060.02363.68-4.14644.578
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A28 - 405
2X-RAY DIFFRACTION2B29 - 405

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