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- PDB-4a55: Crystal structure of p110alpha in complex with iSH2 of p85alpha a... -

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Basic information

Entry
Database: PDB / ID: 4a55
TitleCrystal structure of p110alpha in complex with iSH2 of p85alpha and the inhibitor PIK-108
Components
  • PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT ALPHA
  • PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT ALPHA ISOFORM
KeywordsTRANSFERASE / ONCOGENE / LIPID KINASE / MEMBRANE BINDING / CANCER MUTATIONS / TUMOURS / GROWTH FACTOR SIGNALLING / PI3-KINASE INHIBITOR / NON-ATP COMPETITIVE LIGAND BINDING SITE / STRUCTURE-ACTIVITY RELATIONSHIP / ENZYME REGULATION
Function / homology
Function and homology information


PI3K events in ERBB4 signaling / IRS-mediated signalling / Signaling by ALK / MET activates PI3K/AKT signaling / PI-3K cascade:FGFR3 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / PI-3K cascade:FGFR2 / Signaling by LTK / Costimulation by the CD28 family ...PI3K events in ERBB4 signaling / IRS-mediated signalling / Signaling by ALK / MET activates PI3K/AKT signaling / PI-3K cascade:FGFR3 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / PI-3K cascade:FGFR2 / Signaling by LTK / Costimulation by the CD28 family / PI3K events in ERBB2 signaling / Tie2 Signaling / CD28 dependent PI3K/Akt signaling / PI3K/AKT activation / FLT3 Signaling / GAB1 signalosome / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / TORC2 signaling / RAC2 GTPase cycle / Downstream signal transduction / GPVI-mediated activation cascade / Signaling by SCF-KIT / Role of phospholipids in phagocytosis / RAC1 GTPase cycle / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / G alpha (q) signalling events / Extra-nuclear estrogen signaling / Interleukin receptor SHC signaling / RAF/MAP kinase cascade / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / perinuclear endoplasmic reticulum membrane / response to muscle inactivity / Downstream TCR signaling / regulation of toll-like receptor 4 signaling pathway / Regulation of signaling by CBL / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / Interleukin-3, Interleukin-5 and GM-CSF signaling / IRS-mediated signalling / positive regulation of focal adhesion disassembly / cellular response to hydrostatic pressure / RET signaling / phosphatidylinositol 3-kinase activator activity / autosome genomic imprinting / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulatory subunit binding / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / positive regulation of endoplasmic reticulum unfolded protein response / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / cis-Golgi network / ErbB-3 class receptor binding / VEGFA-VEGFR2 Pathway / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / transmembrane receptor protein tyrosine kinase adaptor activity / regulation of cellular respiration / RHOF GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / RHOD GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / enzyme-substrate adaptor activity / Nephrin family interactions / Signaling by LTK in cancer / Costimulation by the CD28 family / RND1 GTPase cycle / Signaling by LTK / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / relaxation of cardiac muscle / MET activates PI3K/AKT signaling / positive regulation of leukocyte migration / PI3K/AKT activation / RND2 GTPase cycle / DAP12 signaling / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of filopodium assembly / RND3 GTPase cycle / growth hormone receptor signaling pathway / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / negative regulation of stress fiber assembly / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / natural killer cell mediated cytotoxicity / 1-phosphatidylinositol-3-kinase activity
Similarity search - Function
Ubiquitin-like (UB roll) - #770 / Helix Hairpins - #1490 / PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / Phosphatidylinositol 3-/4-kinase, catalytic domain ...Ubiquitin-like (UB roll) - #770 / Helix Hairpins - #1490 / PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 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 / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / 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 / Rho GTPase activation protein / 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 / C2 domain superfamily / SH2 domain / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / Ubiquitin-like (UB roll) / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Alpha Horseshoe / Helix Hairpins / 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
PIK-108 / Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesMUS MUSCULUS (house mouse)
HOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsHon, W.-C. / Berndt, A. / Williams, R.L.
CitationJournal: Oncogene / Year: 2012
Title: Regulation of Lipid Binding Underlies the Activation Mechanism of Class Ia Pi3-Kinases.
Authors: Hon, W.-C. / Berndt, A. / Williams, R.L.
History
DepositionOct 24, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2011Provider: repository / Type: Initial release
Revision 1.1Aug 29, 2012Group: Database references
Revision 1.2Dec 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 ALPHA ISOFORM
B: PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)162,4134
Polymers161,6852
Non-polymers7292
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4400 Å2
ΔGint-23.7 kcal/mol
Surface area52930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)136.092, 147.184, 226.478
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT ALPHA ISOFORM / PI3-KINASE SUBUNIT ALPHA / PI3K-ALPHA / PI3KALPHA / PTDINS-3-KINASE SUBUNIT ALPHA / ...PI3-KINASE SUBUNIT ALPHA / PI3K-ALPHA / PI3KALPHA / PTDINS-3-KINASE SUBUNIT ALPHA / PHOSPHATIDYLINOSITOL-4\ / 5-BISPHOSPHATE 3-KINASE 110 KDA CATALYTIC SUBUNIT ALPHA / PTDINS-3-KINASE SUBUNIT P110-ALPHA / P110ALPHA / PHOSPHOINOSITIDE-3-KINASE CATALYTIC ALPHA POLYPEPTIDE / SERINE/THREONINE PROTEIN KINASE PIK3CA


Mass: 128017.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Plasmid: PFASTBAC / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: P42337, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Protein PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT ALPHA / PI3-KINASE REGULATORY SUBUNIT ALPHA / PI3K REGULATORY SUBUNIT ALPHA / PTDINS-3-KINASE REGULATORY ...PI3-KINASE REGULATORY SUBUNIT ALPHA / PI3K REGULATORY SUBUNIT ALPHA / PTDINS-3-KINASE REGULATORY SUBUNIT ALPHA / PHOSPHATIDYLINOSITOL 3-KINASE 85 KDA REGULATORY SUBUNIT ALPHA / PI3-KINASE SUBUNIT P85-ALPHA / PTDINS-3-KINASE REGULATORY SUBUNIT P85-ALPHA


Mass: 33666.961 Da / Num. of mol.: 1 / Fragment: NISH2, RESIDUES 322-600
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9 / References: UniProt: P27986
#3: Chemical ChemComp-P08 / PIK-108


Mass: 364.438 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24N2O3
Sequence detailsN-TERMINAL TAG WITH HIS6 AND TEV CLEAVAGE SITE ENGINEERED TRUNCATION

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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: 4.2 Å3/Da / Density % sol: 71 % / Description: NONE
Crystal growpH: 6.4
Details: 0.1 M NAK PHOSPHATE PH 6.4, 0.14 M NH4H2SO4, 0.1 M NA FORMATE, 0.42 M NA2SO4, 15% ETHYLENE GLYCOL

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21001
Diffraction source
SourceSiteBeamlineIDWavelength
SYNCHROTRONESRF ID23-210.8726
SYNCHROTRONDiamond I0321
Detector
TypeIDDetectorDate
MARMOSAIC 225 mm CCD1CCDJul 11, 2009
MARMOSAIC 225 mm CCD2CCD
Radiation
IDMonochromatorProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1PT-COATED SI MIRRORSINGLE WAVELENGTHMx-ray1
2PT-COATED SI MIRRORSINGLE WAVELENGTHMx-ray1
Radiation wavelength
IDWavelength (Å)Relative weight
10.87261
211
ReflectionResolution: 3.5→68.3 Å / Num. obs: 29059 / % possible obs: 100 % / Observed criterion σ(I): 1 / Redundancy: 19.2 % / Rmerge(I) obs: 0.28 / Net I/σ(I): 10.2
Reflection shellResolution: 3.5→3.7 Å / Redundancy: 19.6 % / Mean I/σ(I) obs: 1.6 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.7.0002refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2RD0

2rd0


Resolution: 3.5→123.41 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.94 / SU B: 65.193 / SU ML: 0.433 / Cross valid method: THROUGHOUT / ESU R Free: 0.477 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.22777 1484 5.1 %RANDOM
Rwork0.18292 ---
obs0.18528 27571 99.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 122.138 Å2
Baniso -1Baniso -2Baniso -3
1--7.11 Å20 Å20 Å2
2--7.58 Å20 Å2
3----0.47 Å2
Refinement stepCycle: LAST / Resolution: 3.5→123.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9454 0 54 0 9508
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0199719
X-RAY DIFFRACTIONr_bond_other_d0.0020.026810
X-RAY DIFFRACTIONr_angle_refined_deg1.5271.9713119
X-RAY DIFFRACTIONr_angle_other_deg0.9793.00316566
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.07551135
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.21524.236484
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.247151828
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4861568
X-RAY DIFFRACTIONr_chiral_restr0.0780.21421
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02110558
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021978
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 3.5→3.591 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.428 91 -
Rwork0.341 1907 -
obs--99.8 %
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)
11.0996-0.5881-0.2963.3250.16511.3755-0.06140.0490.1229-0.77760.22110.40390.2118-0.3235-0.15970.5451-0.1409-0.05560.4398-0.13090.6463-30.126-66.890320.7808
21.3342-0.0102-0.151.5726-0.06932.23680.0325-0.130.1515-0.28850.01550.0637-0.2426-0.1525-0.0480.0945-0.03830.0530.2433-0.25660.2947-19.0995-35.015634.2128
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A5 - 100
2X-RAY DIFFRACTION1B448 - 597
3X-RAY DIFFRACTION2A101 - 1061

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