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- PDB-6ux9: Crystal Structure Analysis of PIP4K2A -

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Basic information

Entry
Database: PDB / ID: 6ux9
TitleCrystal Structure Analysis of PIP4K2A
ComponentsPhosphatidylinositol 5-phosphate 4-kinase type-2 alpha
KeywordsTRANSFERASE / kinase / SIGNALING PROTEIN
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 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / photoreceptor outer segment / photoreceptor inner segment / negative regulation of insulin receptor signaling pathway / autophagosome / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / lysosome / regulation of autophagy / 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-UHJ / Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.71 Å
AuthorsSeo, H.-S. / Dhe-Paganon, S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery and Structure-Activity Relationship Study of ( Z )-5-Methylenethiazolidin-4-one Derivatives as Potent and Selective Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors.
Authors: Manz, T.D. / Sivakumaren, S.C. / Ferguson, F.M. / Zhang, T. / Yasgar, A. / Seo, H.S. / Ficarro, S.B. / Card, J.D. / Shim, H. / Miduturu, C.V. / Simeonov, A. / Shen, M. / Marto, J.A. / Dhe- ...Authors: Manz, T.D. / Sivakumaren, S.C. / Ferguson, F.M. / Zhang, T. / Yasgar, A. / Seo, H.S. / Ficarro, S.B. / Card, J.D. / Shim, H. / Miduturu, C.V. / Simeonov, A. / Shen, M. / Marto, J.A. / Dhe-Paganon, S. / Hall, M.D. / Cantley, L.C. / Gray, N.S.
History
DepositionNov 7, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 22, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)86,4904
Polymers85,7412
Non-polymers7492
Water6,449358
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2870 Å2
ΔGint-11 kcal/mol
Surface area29590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.230, 88.580, 105.780
Angle α, β, γ (deg.)90.000, 92.910, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 28 through 69 or resid 71...
21(chain B and (resid 28 through 69 or resid 71...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ASNASNTYRTYR(chain A and (resid 28 through 69 or resid 71...AA28 - 6917 - 58
12LYSLYSHISHIS(chain A and (resid 28 through 69 or resid 71...AA71 - 15660 - 145
13ILEILEASPASP(chain A and (resid 28 through 69 or resid 71...AA158 - 223147 - 212
14ASNASNLEULEU(chain A and (resid 28 through 69 or resid 71...AA28 - 40517 - 370
15ASNASNLEULEU(chain A and (resid 28 through 69 or resid 71...AA28 - 40517 - 370
16ASNASNLEULEU(chain A and (resid 28 through 69 or resid 71...AA28 - 40517 - 370
17ASNASNLEULEU(chain A and (resid 28 through 69 or resid 71...AA28 - 40517 - 370
18ASNASNLEULEU(chain A and (resid 28 through 69 or resid 71...AA28 - 40517 - 370
19ASNASNLEULEU(chain A and (resid 28 through 69 or resid 71...AA28 - 40517 - 370
21ASNASNTYRTYR(chain B and (resid 28 through 69 or resid 71...BB28 - 6917 - 58
22LYSLYSPROPRO(chain B and (resid 28 through 69 or resid 71...BB71 - 12360 - 112
23ASNASNASNASN(chain B and (resid 28 through 69 or resid 71...BB124113
24ASNASNLEULEU(chain B and (resid 28 through 69 or resid 71...BB28 - 40517 - 370
25ASNASNLEULEU(chain B and (resid 28 through 69 or resid 71...BB28 - 40517 - 370
26ASNASNLEULEU(chain B and (resid 28 through 69 or resid 71...BB28 - 40517 - 370
27ASNASNLEULEU(chain B and (resid 28 through 69 or resid 71...BB28 - 40517 - 370

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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: 42870.668 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-UHJ / N-[4-(5-{(Z)-[(2E)-2-imino-4-oxo-1,3-thiazolidin-5-ylidene]methyl}pyridin-3-yl)phenyl]methanesulfonamide


Mass: 374.437 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H14N4O3S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 358 / 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: 2.41 Å3/Da / Density % sol: 49.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1M sodium citrate, pH 6.5 12% PEG 5000 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9792 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.71→45.37 Å / Num. obs: 86013 / % possible obs: 97.8 % / Redundancy: 3.4 % / Biso Wilson estimate: 33.766 Å2 / Rpim(I) all: 0.026 / Rrim(I) all: 0.048 / Net I/σ(I): 12.4 / Num. measured all: 291606
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
1.71-1.743.51.21474242520.7031.33697.7
4.64-45.383.4321459343340.0180.03396

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.16_3549refinement
PDB_EXTRACT3.25data extraction
xia2data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6OSP

6osp


Resolution: 1.71→45.368 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 28.47
RfactorNum. reflection% reflection
Rfree0.2036 4197 4.89 %
Rwork0.1771 --
obs0.1784 85905 97.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 143.11 Å2 / Biso mean: 51.9078 Å2 / Biso min: 25.33 Å2
Refinement stepCycle: final / Resolution: 1.71→45.368 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5174 0 78 358 5610
Biso mean--49.39 49.78 -
Num. residues----628
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1824X-RAY DIFFRACTION6.84TORSIONAL
12B1824X-RAY DIFFRACTION6.84TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.71-1.72940.45981270.4099268698
1.7294-1.74980.44251140.3977273098
1.7498-1.77110.41411250.3769279597
1.7711-1.79350.39031270.3461268398
1.7935-1.81710.33181210.3087270898
1.8171-1.8420.30621500.2903277598
1.842-1.86840.33291410.2788267998
1.8684-1.89620.28431400.2401272198
1.8962-1.92590.26671590.2343272598
1.9259-1.95740.25051400.213266398
1.9574-1.99120.22311360.2012274098
1.9912-2.02740.22481570.1938270898
2.0274-2.06640.22441420.1916275699
2.0664-2.10860.26141600.1933273798
2.1086-2.15440.2161330.1908272398
2.1544-2.20450.24331590.1858277799
2.2045-2.25970.22531260.1781268899
2.2597-2.32080.22331320.1813277198
2.3208-2.38910.23331340.172271198
2.3891-2.46620.17051450.1788279099
2.4662-2.55430.20831470.1828271899
2.5543-2.65660.23411410.182272898
2.6566-2.77750.2381520.1906276198
2.7775-2.92390.22281540.19269898
2.9239-3.1070.25851220.1897271197
3.107-3.34680.18771300.1696272497
3.3468-3.68350.18871460.1678271196
3.6835-4.21620.16481430.1414265296
4.2162-5.31060.15291200.131272496
5.3106-45.36380.16981740.1686271596
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)
12.90440.4325-0.94971.0983-0.34732.2851-0.0679-0.1712-0.05370.0371-0.0323-0.00860.0173-0.14320.11160.35270.00270.00680.2619-0.01740.332911.9943-9.963611.7484
21.9019-0.1684-0.23540.7513-0.58573.2765-0.1040.1796-0.1478-0.0899-0.05040.02420.1019-0.22440.15750.3271-0.00850.0070.2145-0.03040.341415.2626-7.4088-2.4449
35.40362.7619-0.81775.4413-2.01383.8656-0.07620.8901-0.1744-0.4433-0.04230.89650.2465-0.92590.06830.4435-0.0205-0.05120.584-0.13620.43557.5868-3.5389-23.0545
44.6872-1.73210.18595.2261-0.61884.2056-0.12740.18710.2291-0.3121-0.0481-0.2276-0.13090.00440.14910.3286-0.0093-0.01430.2039-0.01850.26220.43640.4585-15.1773
54.2639-0.88460.50454.6229-1.04646.504-0.27010.00020.95710.31550.06920.1385-1.2623-0.42290.0890.62630.0738-0.07830.35850.03130.646212.384713.8329-11.5916
65.1382-1.2089-0.80213.39760.23325.5139-0.13720.4588-0.6756-0.143-0.0469-0.16640.70330.31670.11190.4140.00280.02680.3484-0.04560.386621.0218-7.695-18.6047
76.1591-0.94130.07951.8849-0.40393.5034-0.0629-0.04470.15260.083-0.1101-0.2393-0.19330.35440.05430.3634-0.03320.00670.33130.02430.388115.7482-11.389128.5456
82.7504-0.3904-2.38470.8470.12772.7344-0.07650.0447-0.0903-0.0191-0.04450.06050.1222-0.20290.15230.3786-0.024-0.00460.37410.01630.39065.812-15.828527.5156
98.3472-0.5645-1.10962.34940.96625.02560.1129-0.20570.0196-0.137-0.0735-0.1693-0.08230.2999-0.00360.3795-0.0751-0.02280.42670.00740.360813.4865-8.600538.5906
103.26090.1632-0.53241.3937-0.25443.8435-0.2137-0.5997-0.33850.0621-0.06410.01850.18760.00980.27590.355-0.01320.03050.41230.06520.33253.6567-16.089842.2329
112.4802-0.01850.05093.34370.29784.65520.0303-0.7851-0.2476-0.01030.0273-0.4428-0.21390.33480.16990.2809-0.00410.02190.59740.08230.403913.2709-13.698448.8692
124.3024-1.5115-0.52584.76751.4384.0718-0.1531-1.1056-0.40320.684-0.0557-0.77790.42750.75120.19210.59310.0919-0.03191.08690.27990.648213.7796-18.708365.2575
133.62920.98340.38292.09740.31913.1376-0.2041-0.88580.07580.0822-0.01940.26290.0313-0.31680.16040.45720.01690.02770.81170.06180.3688-1.4299-14.230958.0676
141.701-0.31060.21621.7141.25866.0323-0.1194-0.71710.15480.06050.0791-0.2712-0.87030.51130.0230.5434-0.0356-0.04440.7981-0.06830.353210.0671-1.123760.469
155.23740.2371-1.39123.0322-0.027.1869-0.2639-1.081-0.61660.6319-0.04810.46160.78150.02060.13970.6295-0.01960.05731.03190.28270.5462-1.4311-23.84460.2725
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 28 through 133 )A28 - 133
2X-RAY DIFFRACTION2chain 'A' and (resid 134 through 212 )A134 - 212
3X-RAY DIFFRACTION3chain 'A' and (resid 213 through 248 )A213 - 248
4X-RAY DIFFRACTION4chain 'A' and (resid 249 through 287 )A249 - 287
5X-RAY DIFFRACTION5chain 'A' and (resid 288 through 350 )A288 - 350
6X-RAY DIFFRACTION6chain 'A' and (resid 351 through 405 )A351 - 405
7X-RAY DIFFRACTION7chain 'B' and (resid 28 through 54 )B28 - 54
8X-RAY DIFFRACTION8chain 'B' and (resid 55 through 104 )B55 - 104
9X-RAY DIFFRACTION9chain 'B' and (resid 105 through 133 )B105 - 133
10X-RAY DIFFRACTION10chain 'B' and (resid 134 through 186 )B134 - 186
11X-RAY DIFFRACTION11chain 'B' and (resid 187 through 212 )B187 - 212
12X-RAY DIFFRACTION12chain 'B' and (resid 213 through 248 )B213 - 248
13X-RAY DIFFRACTION13chain 'B' and (resid 249 through 282 )B249 - 282
14X-RAY DIFFRACTION14chain 'B' and (resid 283 through 358 )B283 - 358
15X-RAY DIFFRACTION15chain 'B' and (resid 359 through 405 )B359 - 405

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