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- PDB-8am0: Crystal structure of human T1061E PI3Kalpha in complex with its r... -

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Basic information

Entry
Database: PDB / ID: 8am0
TitleCrystal structure of human T1061E PI3Kalpha in complex with its regulatory subunit and the inhibitor GDC-0077 (Inavolisib)
Components
  • Isoform 3 of Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE / lipid kinase / phosphoinositide / 3-kinase / signaling
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / cellular response to hydrostatic pressure / autosome genomic imprinting / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K ...response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / cellular response to hydrostatic pressure / autosome genomic imprinting / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / vasculature development / regulation of cellular respiration / Signaling by cytosolic FGFR1 fusion mutants / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / Nephrin family interactions / anoikis / relaxation of cardiac muscle / Signaling by LTK in cancer / Costimulation by the CD28 family / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / Signaling by LTK / MET activates PI3K/AKT signaling / phosphatidylinositol-4,5-bisphosphate 3-kinase / PI3K/AKT activation / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / negative regulation of macroautophagy / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / PI-3K cascade:FGFR4 / response to dexamethasone / PI-3K cascade:FGFR1 / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / CD28 dependent PI3K/Akt signaling / phosphatidylinositol phosphate biosynthetic process / PI3K events in ERBB2 signaling / PI3K Cascade / negative regulation of anoikis / intercalated disc / RET signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / regulation of multicellular organism growth / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / GAB1 signalosome / Role of phospholipids in phagocytosis / Role of LAT2/NTAL/LAB on calcium mobilization / adipose tissue development / Interleukin receptor SHC signaling / positive regulation of lamellipodium assembly / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / phagocytosis / Signaling by FGFR4 in disease / phosphorylation / cardiac muscle contraction / energy homeostasis / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR2 in disease / Signaling by FGFR3 in disease / Tie2 Signaling / GPVI-mediated activation cascade / T cell costimulation / FLT3 Signaling / response to muscle stretch / Signaling by FLT3 fusion proteins / RAC1 GTPase cycle / Signaling by FGFR1 in disease / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Downstream signal transduction / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / liver development / insulin-like growth factor receptor signaling pathway / response to activity / Regulation of signaling by CBL / cellular response to glucose stimulus / positive regulation of smooth muscle cell proliferation / regulation of protein phosphorylation / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by SCF-KIT / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / platelet activation / VEGFA-VEGFR2 Pathway
Similarity search - Function
PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding 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 / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / PI3-kinase family, ras-binding domain / C2 phosphatidylinositol 3-kinase-type domain ...PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding 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 / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / PI3-kinase family, ras-binding domain / C2 phosphatidylinositol 3-kinase-type domain / 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 C2 / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / 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 / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-MWF / TRIETHYLENE GLYCOL / Isoform 3 of Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.818 Å
AuthorsGoncalves, M. / Johnson, J.L. / Roewer, K.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 CA197588 United States
CitationJournal: Cell Rep / Year: 2023
Title: Epinephrine inhibits PI3K alpha via the Hippo kinases.
Authors: Lin, T.Y. / Ramsamooj, S. / Perrier, T. / Liberatore, K. / Lantier, L. / Vasan, N. / Karukurichi, K. / Hwang, S.K. / Kesicki, E.A. / Kastenhuber, E.R. / Wiederhold, T. / Yaron, T.M. / ...Authors: Lin, T.Y. / Ramsamooj, S. / Perrier, T. / Liberatore, K. / Lantier, L. / Vasan, N. / Karukurichi, K. / Hwang, S.K. / Kesicki, E.A. / Kastenhuber, E.R. / Wiederhold, T. / Yaron, T.M. / Huntsman, E.M. / Zhu, M. / Ma, Y. / Paddock, M.N. / Zhang, G. / Hopkins, B.D. / McGuinness, O. / Schwartz, R.E. / Ersoy, B.A. / Cantley, L.C. / Johnson, J.L. / Goncalves, M.D.
History
DepositionAug 2, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 3, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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

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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: Isoform 3 of Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,4548
Polymers159,6752
Non-polymers7796
Water3,405189
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7920 Å2
ΔGint-17 kcal/mol
Surface area57590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.81, 107.68, 136.3
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 2 molecules AB

#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 alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 124473.000 Da / Num. of mol.: 1 / Mutation: T1061E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P42336, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Protein Isoform 3 of 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: 35201.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27986-3

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Non-polymers , 5 types, 195 molecules

#3: Chemical ChemComp-MWF / (2R)-2-[[2-[(4S)-4-[bis(fluoranyl)methyl]-2-oxidanylidene-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide / Inavolisib


Mass: 407.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19F2N5O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 189 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 3

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Sample preparation

Crystal
IDDensity Matthews (Å3/Da)Density % sol (%)
12.2946.37
2
3
Crystal grow
Temperature (K)Crystal-IDMethodpHDetails
2931vapor diffusion, hanging drop8.10.10 M Bis-Tris-Propane pH 8.10, 0.20 M Na 3 -citrate, 10.00 %(w/v) PEG 3350
2932vapor diffusion, hanging drop8.10.10 M Bis-Tris-Propane pH 8.10, 0.20 M Na 3 -citrate, 10.00 %(w/v) PEG 3350
2933vapor diffusion, hanging drop8.10.10 M Bis-Tris-Propane pH 8.10, 0.20 M Na 3 -citrate, 10.00 %(w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.436→47.386 Å / Num. obs: 44827 / % possible obs: 80.7 % / Redundancy: 18.6 % / CC1/2: 0.996 / Rpim(I) all: 0.066 / Rrim(I) all: 0.284 / Net I/σ(I): 8.2
Reflection shellResolution: 2.436→2.626 Å / Redundancy: 19.1 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 2241 / CC1/2: 0.648 / Rpim(I) all: 0.546 / Rrim(I) all: 2.395 / % possible all: 20.3

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4L1B

4l1b


Resolution: 2.818→47.39 Å / Cor.coef. Fo:Fc: 0.878 / Cor.coef. Fo:Fc free: 0.867 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.455
RfactorNum. reflection% reflectionSelection details
Rfree0.3 1768 -RANDOM
Rwork0.2854 ---
obs0.2861 36173 100 %-
Displacement parametersBiso mean: 69.9 Å2
Baniso -1Baniso -2Baniso -3
1-5.4524 Å20 Å20 Å2
2--7.0528 Å20 Å2
3----12.5052 Å2
Refine analyzeLuzzati coordinate error obs: 0.52 Å
Refinement stepCycle: LAST / Resolution: 2.818→47.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10604 0 52 189 10845
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00721471HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.7538817HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d6488SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes3357HARMONIC5
X-RAY DIFFRACTIONt_it10880HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1371SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact16389SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion1.79
X-RAY DIFFRACTIONt_other_torsion14.49
LS refinement shellResolution: 2.82→2.84 Å
RfactorNum. reflection% reflection
Rfree0.3322 37 -
Rwork0.3631 --
obs0.3614 724 100 %
Refinement TLS params.

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)
10.71960.27450.08570.4322-0.03860.34540.04380.06580.03340.0658-0.033-0.02740.0334-0.0274-0.0108-0.08250.0147-0.0222-0.0823-0.0096-0.079310.1254-27.2311-28.0495
20.57950.2184-0.33290.6608-0.2920.13150.0254-0.0017-0.0485-0.0017-0.0078-0.0238-0.0485-0.0238-0.0177-0.1314-0.0396-0.0068-0.0691-0.0234-0.085214.3956-15.7222-50.1166
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A2 - 1062
2X-RAY DIFFRACTION1{ A|* }A2001 - 2301
3X-RAY DIFFRACTION2{ B|* }B329 - 590

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