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- PDB-2x38: The crystal structure of the murine class IA PI 3-kinase p110delt... -

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Basic information

Entry
Database: PDB / ID: 2x38
TitleThe crystal structure of the murine class IA PI 3-kinase p110delta in complex with IC87114.
ComponentsPHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM
KeywordsTRANSFERASE / PHOSPHOINOSITIDE 3-KINASE / 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-IC8 / 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: 2.2 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
DepositionJan 22, 2010Deposition site: PDBE / Processing site: PDBE
SupersessionFeb 2, 2010ID: 2WXE
Revision 1.0Feb 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / 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_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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)108,2212
Polymers107,8241
Non-polymers3971
Water72140
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.420, 64.660, 116.900
Angle α, β, γ (deg.)90.00, 103.39, 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-IC8 / 2-[(6-AMINO-9H-PURIN-9-YL)METHYL]-5-METHYL-3-(2-METHYLPHENYL)QUINAZOLIN-4(3H)-ONE


Mass: 397.433 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H19N7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / 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: 49.76 % / Description: NONE
Crystal growpH: 6.8
Details: 20% (V/V) GLYCEROL, 10% (V/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: Diamond / Beamline: I02 / Wavelength: 0.9791
DetectorType: ADSC CCD / Detector: CCD / Date: Jan 21, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.2→56.89 Å / Num. obs: 51811 / % possible obs: 98.4 % / Observed criterion σ(I): -3.7 / Redundancy: 3.53 % / Biso Wilson estimate: 37.612 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 13.92
Reflection shellResolution: 2.2→2.22 Å / Redundancy: 3.56 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 2.62 / % possible all: 97.7

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Processing

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

2rd0


Resolution: 2.2→56.89 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.88 / SU B: 14.695 / SU ML: 0.173 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.286 / ESU R Free: 0.227 / 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
Rfree0.27719 1578 3 %RANDOM
Rwork0.23852 ---
obs0.2397 50232 98.06 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.467 Å2
Baniso -1Baniso -2Baniso -3
1-0.26 Å20 Å20.04 Å2
2--0.41 Å20 Å2
3----0.65 Å2
Refinement stepCycle: LAST / Resolution: 2.2→56.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6633 0 30 40 6703
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0226817
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.251.9699203
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4485813
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.04723.956316
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.653151231
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.91541
X-RAY DIFFRACTIONr_chiral_restr0.0820.21012
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215079
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2110.23187
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3040.24696
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1460.2209
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2170.243
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2820.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5361.54097
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.99826586
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.63432720
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.5274.52617
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: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.314 107 -
Rwork0.259 3715 -
obs--97.7 %
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)
12.37720.08571.26851.02460.10553.8288-0.05050.18020.3386-0.04560.0398-0.0463-0.6501-0.11280.01060.2680.09330.00320.09980.0470.25-14.00833.52920.337
24.35080.32611.50412.5479-0.48284.23430.2865-0.1055-0.32620.2502-0.0639-0.3227-0.13470.8912-0.22260.23610.0293-0.08070.3622-0.03250.35119.17826.39638.14
33.1619-0.2403-1.51661.85180.94995.90530.02910.99080.3258-0.163-0.00360.247-0.2142-2.2071-0.02540.17340.3048-0.02541.38950.13950.2101-48.84324.78415.295
42.57-0.1213-1.06890.72140.0632.55120.0005-0.1880.26950.16120.05870.1663-0.4911-0.6588-0.05910.21350.24460.0140.36650.0230.2011-31.9526.83833.693
50.8413-0.0688-0.46521.3861-0.38893.0914-0.0520.0813-0.10610.0990.0360.04110.3875-0.23610.01610.091-0.0015-0.01880.048-0.02710.0734-11.2762.31730.777
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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