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Basic information

Entry
Database: PDB / ID: 5dxt
Titlep110alpha with GDC-0326
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTransferase/Inhibitor / lipid kinase / Transferase-Inhibitor complex
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 / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / 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 / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / 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 / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IB / vasculature development / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / phosphatidylinositol 3-kinase complex, class IA / anoikis / phosphatidylinositol 3-kinase complex / Nephrin family interactions / Costimulation by the CD28 family / relaxation of cardiac muscle / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / MET activates PI3K/AKT signaling / PI3K/AKT activation / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / negative regulation of macroautophagy / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / response to dexamethasone / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / PI3K events in ERBB2 signaling / negative regulation of anoikis / intercalated disc / RET signaling / regulation of multicellular organism growth / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / Role of phospholipids in phagocytosis / GAB1 signalosome / Role of LAT2/NTAL/LAB on calcium mobilization / adipose tissue development / Interleukin receptor SHC signaling / positive regulation of lamellipodium assembly / phagocytosis / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / energy homeostasis / Signaling by FGFR4 in disease / cardiac muscle contraction / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR3 in disease / GPVI-mediated activation cascade / Tie2 Signaling / Signaling by FGFR2 in disease / RAC1 GTPase cycle / T cell costimulation / response to muscle stretch / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Downstream signal transduction / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / phosphatidylinositol 3-kinase/protein kinase B signal transduction / liver development / 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 ALK fusions and activated point mutants / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / platelet activation / VEGFA-VEGFR2 Pathway / cellular response to insulin stimulus / Constitutive Signaling by Aberrant PI3K in Cancer
Similarity search - Function
PI3Kalpha, 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 ...PI3Kalpha, 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. / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain / C2 phosphatidylinositol 3-kinase-type domain / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / 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 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / 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-5H5 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsHeffron, T.P. / Heald, R.A. / Ndubaku, C. / Wei, B.Q. / Augustin, M. / Do, S. / Edgar, K. / Eigenbrot, C. / Friedman, L. / Gancia, E. ...Heffron, T.P. / Heald, R.A. / Ndubaku, C. / Wei, B.Q. / Augustin, M. / Do, S. / Edgar, K. / Eigenbrot, C. / Friedman, L. / Gancia, E. / Jackson, P.S. / Jones, G. / Kolesnikov, A. / Lee, L.B. / Lesnick, J.D. / Lewis, C. / McLean, N. / Mortle, M. / Nonomiya, J. / Pang, J. / Price, S. / Prior, W.W. / Salphati, L. / Sideris, S. / Staben, S.T. / Steinbacher, S. / Tsui, V. / Wallin, J. / Sampath, D. / Olivero, A.
CitationJournal: J.Med.Chem. / Year: 2016
Title: The Rational Design of Selective Benzoxazepin Inhibitors of the alpha-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)- ...Title: The Rational Design of Selective Benzoxazepin Inhibitors of the alpha-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326).
Authors: Heffron, T.P. / Heald, R.A. / Ndubaku, C. / Wei, B. / Augistin, M. / Do, S. / Edgar, K. / Eigenbrot, C. / Friedman, L. / Gancia, E. / Jackson, P.S. / Jones, G. / Kolesnikov, A. / Lee, L.B. / ...Authors: Heffron, T.P. / Heald, R.A. / Ndubaku, C. / Wei, B. / Augistin, M. / Do, S. / Edgar, K. / Eigenbrot, C. / Friedman, L. / Gancia, E. / Jackson, P.S. / Jones, G. / Kolesnikov, A. / Lee, L.B. / Lesnick, J.D. / Lewis, C. / McLean, N. / Mortl, M. / Nonomiya, J. / Pang, J. / Price, S. / Prior, W.W. / Salphati, L. / Sideris, S. / Staben, S.T. / Steinbacher, S. / Tsui, V. / Wallin, J. / Sampath, D. / Olivero, A.G.
History
DepositionSep 23, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 27, 2016Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2016Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,4983
Polymers112,0541
Non-polymers4442
Water3,567198
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.507, 133.672, 141.339
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / p110alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 112053.500 Da / Num. of mol.: 1 / Fragment: PI3-KINASE P110 ALPHA, UNP residues 107-1068
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-5H5 / (2S)-2-({2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl}oxy)propanamide / GDC-0326


Mass: 382.416 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22N6O3
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 198 / 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: 2.6 Å3/Da / Density % sol: 52.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: PEG 20000 / PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99988 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 13, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99988 Å / Relative weight: 1
ReflectionResolution: 2.25→97.12 Å / Num. obs: 51953 / % possible obs: 96.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 2.9 % / Rsym value: 0.051 / Net I/σ(I): 12.8
Reflection shellResolution: 2.25→2.33 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.356 / Mean I/σ(I) obs: 2.9 / % possible all: 97.6

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.2.0005refinement
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→97.12 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.928 / SU B: 13.795 / SU ML: 0.184 / Cross valid method: THROUGHOUT / ESU R: 0.3 / ESU R Free: 0.227 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26196 1388 2.7 %RANDOM
Rwork0.22721 ---
obs0.22812 50478 97.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 70.252 Å2
Baniso -1Baniso -2Baniso -3
1-1.04 Å20 Å20 Å2
2--1.54 Å20 Å2
3----2.59 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.227 Å0.3 Å
Refinement stepCycle: LAST / Resolution: 2.25→97.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7187 0 32 198 7417
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0227163
X-RAY DIFFRACTIONr_bond_other_d0.0020.026422
X-RAY DIFFRACTIONr_angle_refined_deg1.0511.969714
X-RAY DIFFRACTIONr_angle_other_deg0.882314875
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0665869
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.13224.277332
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.798151209
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.931540
X-RAY DIFFRACTIONr_chiral_restr0.0610.21073
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.027910
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021440
X-RAY DIFFRACTIONr_nbd_refined0.1490.21328
X-RAY DIFFRACTIONr_nbd_other0.1260.26169
X-RAY DIFFRACTIONr_nbtor_refined0.1540.23377
X-RAY DIFFRACTIONr_nbtor_other0.0730.23674
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0780.2260
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0690.25
X-RAY DIFFRACTIONr_symmetry_vdw_other0.0940.233
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1110.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.06825703
X-RAY DIFFRACTIONr_mcbond_other0.15821757
X-RAY DIFFRACTIONr_mcangle_it1.27337063
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.84743280
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.60362651
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: 2.25→2.308 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 115 -
Rwork0.303 3667 -
obs--97.93 %
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)
11.5293-1.6732-0.77383.1028-0.40092.2009-0.0047-0.4420.02940.80360.0531-0.44080.28980.5789-0.0484-0.13010.0436-0.0285-0.0276-0.0313-0.123516.251-3.45336.974
21.8732.0862-1.61612.8093-0.68054.8555-0.160.2807-0.2526-0.20070.12280.0671.0756-0.27490.03710.1936-0.01470.0274-0.2265-0.0347-0.1168.641-19.8243.953
30.8857-0.1226-1.14430.17490.17384.25760.05630.09610.0524-0.08730.0214-0.0535-0.22940.2795-0.0776-0.262-0.0184-0.0011-0.1997-0.0333-0.199316.0263.978.438
41.7478-0.62530.60441.5706-0.68623.24280.0535-0.2221-0.07360.07450.09930.3035-0.0315-0.5538-0.1529-0.25840.03490.0078-0.1327-0.037-0.1871-10.6796.62534.236
55.188212.517-5.218730.9197-12.51755.25680.21160.01310.79190.4317-0.86550.694-0.7538-0.03660.6539-0.0060.10110.0555-0.064-0.1271-0.0103-3.62121.96745.299
64.3186-1.2786-0.95872.66820.4742.9038-0.05280.35740.2291-0.20480.10510.3164-0.3976-0.4869-0.0523-0.11720.0448-0.0372-0.09030.0928-0.111-13.75321.25512.83
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A107 - 165
2X-RAY DIFFRACTION1A291 - 310
3X-RAY DIFFRACTION2A322 - 487
4X-RAY DIFFRACTION3A488 - 699
5X-RAY DIFFRACTION4A700 - 785
6X-RAY DIFFRACTION4A796 - 850
7X-RAY DIFFRACTION5A786 - 795
8X-RAY DIFFRACTION6A851 - 1333

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