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- PDB-2wxf: The crystal structure of the murine class IA PI 3-kinase p110delt... -

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Basic information

Entry
Database: PDB / ID: 2wxf
TitleThe crystal structure of the murine class IA PI 3-kinase p110delta in complex with PIK-39.
ComponentsPHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM
KeywordsTRANSFERASE / PHOSPHOPROTEIN / ISOFORM-SPECIFIC INHIBITORS / CANCER
Function / homology
Function and homology information


Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / phosphatidylinositol 3-kinase complex ...Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / phosphatidylinositol 3-kinase complex / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / B cell homeostasis / B cell activation / phosphatidylinositol-mediated signaling / homeostasis of number of cells / defense response to fungus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of angiogenesis / chemotaxis / kinase activity / adaptive immune response / cell differentiation / cell surface receptor signaling pathway / inflammatory response / negative regulation of gene expression / innate immune response / positive regulation of gene expression / ATP binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PI3Kdelta, catalytic domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain ...PI3Kdelta, catalytic domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / C2 domain superfamily / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Ubiquitin-like (UB roll) / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Roll / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-039 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / phosphatidylinositol-4,5-bisphosphate 3-kinase
Similarity search - Component
Biological speciesMUS MUSCULUS (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsBerndt, A. / Miller, S. / Williams, O. / Lee, D.D. / Houseman, B.T. / Pacold, J.I. / Gorrec, F. / Hon, W.-C. / Liu, Y. / Rommel, C. ...Berndt, A. / Miller, S. / Williams, O. / Lee, D.D. / Houseman, B.T. / Pacold, J.I. / Gorrec, F. / Hon, W.-C. / Liu, Y. / Rommel, C. / Gaillard, P. / Ruckle, T. / Schwarz, M.K. / Shokat, K.M. / Shaw, J.P. / Williams, R.L.
CitationJournal: Nat.Chem.Biol. / Year: 2010
Title: The P110D Structure: Mechanisms for Selectivity and Potency of New Pi(3)K Inhibitors
Authors: Berndt, A. / Miller, S. / Williams, O. / Lee, D.D. / Houseman, B.T. / Pacold, J.I. / Gorrec, F. / Hon, W.-C. / Liu, Y. / Rommel, C. / Gaillard, P. / Ruckle, T. / Schwarz, M.K. / Shokat, K.M. ...Authors: Berndt, A. / Miller, S. / Williams, O. / Lee, D.D. / Houseman, B.T. / Pacold, J.I. / Gorrec, F. / Hon, W.-C. / Liu, Y. / Rommel, C. / Gaillard, P. / Ruckle, T. / Schwarz, M.K. / Shokat, K.M. / Shaw, J.P. / Williams, R.L.
History
DepositionNov 9, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 12, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Apr 24, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc / pdbx_database_status
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_sheet / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_sheet.number_strands / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,2752
Polymers107,8241
Non-polymers4511
Water4,360242
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.420, 65.010, 116.690
Angle α, β, γ (deg.)90.00, 103.53, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM / PI3-KINASE P110 SUBUNIT DELTA / PTDINS-3-KINASE P110 / P110DELTA / PI3K


Mass: 107823.664 Da / Num. of mol.: 1 / Fragment: RESIDUES 106-1044
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Plasmid: PFASTBAC HTA / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q3UDT3, UniProt: O35904*PLUS, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-039 / 2-((9H-PURIN-6-YLTHIO)METHYL)-5-CHLORO-3-(2-METHOXYPHENYL)QUINAZOLIN-4(3H)-ONE / PIK-39


Mass: 450.901 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H15ClN6O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 242 / Source method: isolated from a natural source / Formula: H2O

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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: 2.45 Å3/Da / Density % sol: 49.9 % / Description: NONE
Crystal growpH: 6.8
Details: 20% (V/V) GLYCEROL, 10% (W/V) PEG 4K, 30 MM NANO3, 30 MM NA2HPO4, 30 MM (NH4)2SO4, 100 MM IMIDAZOLE PH 6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.97
DetectorType: ADSC CCD / Detector: CCD / Date: Jul 20, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.9→38.95 Å / Num. obs: 80511 / % possible obs: 98.5 % / Observed criterion σ(I): -3.7 / Redundancy: 6.79 % / Biso Wilson estimate: 31.476 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 16.31
Reflection shellResolution: 1.9→1.92 Å / Redundancy: 6.77 % / Rmerge(I) obs: 0.84 / Mean I/σ(I) obs: 1.78 / % possible all: 96.3

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Processing

Software
NameVersionClassification
REFMAC5.5.0046refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2RD0

2rd0


Resolution: 1.9→38.95 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.927 / SU B: 7.66 / SU ML: 0.105 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.15 / ESU R Free: 0.138 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. ATOM RECORD CONTAINS RESIDUAL B FACTORS ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.23986 2436 3 %RANDOM
Rwork0.2096 ---
obs0.21052 78074 98.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.363 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20 Å20.13 Å2
2--0.57 Å20 Å2
3----1.08 Å2
Refinement stepCycle: LAST / Resolution: 1.9→38.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6633 0 31 242 6906
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0226818
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2531.9699203
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1895813
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.98123.956316
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.926151231
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8481541
X-RAY DIFFRACTIONr_chiral_restr0.0870.21012
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215078
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2010.23215
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3020.24712
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1630.2327
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2380.232
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0950.210
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.661.54097
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.22926586
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.04632721
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.2064.52617
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.901→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.307 184 -
Rwork0.274 5588 -
obs--95.94 %
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)
12.84780.06271.29080.75450.11494.06930.01550.20880.2655-0.00570.13910.0058-0.8832-0.3467-0.15460.42150.17650.020.12920.08940.2792-13.93233.67620.287
25.0834-0.70830.82922.651-1.15163.89140.1865-0.4946-0.19330.1387-0.0732-0.2825-0.29830.7867-0.11330.2448-0.0187-0.06780.3329-0.06250.29169.22926.43538.083
33.174-0.1839-1.84832.04092.05227.79030.42211.59660.3612-0.307-0.42390.1817-0.9704-3.71280.00180.30740.7065-0.0362.50680.22670.3202-48.80625.08815.25
42.04750-0.97380.84220.0592.89160.0764-0.05980.23670.16860.0550.1575-0.6275-0.9794-0.13140.28280.32890.02610.50670.06750.2102-31.89927.06233.645
50.70380.0862-0.47091.3185-0.31373.0024-0.04550.0682-0.06890.09220.05940.01720.4636-0.2706-0.01390.17740.003-0.04660.0523-0.01350.0947-11.3292.4430.719
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A109 - 189
2X-RAY DIFFRACTION2A190 - 290
3X-RAY DIFFRACTION3A317 - 494
4X-RAY DIFFRACTION4A511 - 677
5X-RAY DIFFRACTION5A678 - 1027

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