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- PDB-9yf2: Crystal structure of PI3Ka H1047R mutant in complex with PRT7140 ... -

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Basic information

Entry
Database: PDB / ID: 9yf2
TitleCrystal structure of PI3Ka H1047R mutant in complex with PRT7140 in allosteric pocket
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsONCOPROTEIN / PI3Ka / P110-P85 complex / H1047R mutant
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / 1-phosphatidylinositol-3-kinase regulator activity / T follicular helper cell differentiation / phosphatidylinositol 3-kinase activator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol kinase activity / regulation of actin filament organization / phosphatidylinositol 3-kinase regulator activity ...perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / 1-phosphatidylinositol-3-kinase regulator activity / T follicular helper cell differentiation / phosphatidylinositol 3-kinase activator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol kinase activity / regulation of actin filament organization / phosphatidylinositol 3-kinase regulator activity / response to butyrate / negative regulation of actin filament depolymerization / IRS-mediated signalling / phosphatidylinositol 3-kinase regulatory subunit binding / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / neurotrophin TRKA receptor binding / positive regulation of focal adhesion disassembly / response to L-leucine / cellular response to hydrostatic pressure / cis-Golgi network / Activated NTRK2 signals through PI3K / transmembrane receptor protein tyrosine kinase adaptor activity / ErbB-3 class receptor binding / negative regulation of stress fiber assembly / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / phosphatidylinositol 3-kinase complex / TORC2 signaling / Co-stimulation by ICOS / positive regulation of protein localization to membrane / Signaling by cytosolic FGFR1 fusion mutants / RHOD GTPase cycle / vasculature development / positive regulation of filopodium assembly / Nephrin family interactions / RHOF GTPase cycle / Signaling by LTK in cancer / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by LTK / kinase activator activity / anoikis / RND1 GTPase cycle / RND2 GTPase cycle / phosphatidylinositol 3-kinase complex, class IA / MET activates PI3K/AKT signaling / RND3 GTPase cycle / PI3K/AKT activation / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / growth hormone receptor signaling pathway / relaxation of cardiac muscle / natural killer cell mediated cytotoxicity / insulin binding / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by ALK / cardiac muscle cell contraction / RHOV GTPase cycle / GP1b-IX-V activation signalling / RHOB GTPase cycle / vascular endothelial growth factor signaling pathway / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / negative regulation of macroautophagy / response to dexamethasone / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / positive regulation of protein kinase activity / RHOU GTPase cycle / response to muscle stretch / phosphatidylinositol-mediated signaling / RET signaling / CDC42 GTPase cycle / T cell differentiation / negative regulation of anoikis / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K events in ERBB2 signaling / RHOG GTPase cycle / insulin receptor substrate binding / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / RAC3 GTPase cycle / RHOA GTPase cycle / RAC2 GTPase cycle / Interleukin receptor SHC signaling / intercalated disc / Role of phospholipids in phagocytosis / CD28 dependent PI3K/Akt signaling / positive regulation of TOR signaling / GAB1 signalosome / endothelial cell migration / enzyme-substrate adaptor activity / substrate adhesion-dependent cell spreading
Similarity search - Function
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 / PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein 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 / PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / 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 / 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. / Rho GTPase activation protein / 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 3/4-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 / C2 domain superfamily / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Chem-X3N / 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: 3.61 Å
AuthorsWang, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2026
Title: Discovery of Tetrasubstituted Quinazolin-4(3 H )-ones as Wild-type-sparing, Highly Selective PI3K alpha H1047R Inhibitors
Authors: Chen, C. / Holmes, R. / Carter, J. / Maity, S. / Pawley, S. / Stahl, N. / Crossan, A. / Rager, J. / Juvekar, A. / Wang, M. / Xu, C. / Kuskovsky, R. / Sivakumar, M. / Gallagher, K. / Leal, R. ...Authors: Chen, C. / Holmes, R. / Carter, J. / Maity, S. / Pawley, S. / Stahl, N. / Crossan, A. / Rager, J. / Juvekar, A. / Wang, M. / Xu, C. / Kuskovsky, R. / Sivakumar, M. / Gallagher, K. / Leal, R. / Geeganage, S. / Scherle, P. / Combs, A. / Buesking, A.
History
DepositionSep 25, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 30, 2026Provider: repository / Type: Initial release

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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
C: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)156,9334
Polymers156,0012
Non-polymers9322
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5720 Å2
ΔGint-21 kcal/mol
Surface area59220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.990, 125.780, 167.450
Angle α, β, γ (deg.)90.00, 91.50, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
11A
21A
12C
22C

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11PROPROPHEPHEAA3 - 10593 - 1059
21PROPROPHEPHEAA3 - 10593 - 1059
12ASNASNTRPTRPCB323 - 5831 - 261
22ASNASNTRPTRPCB323 - 5831 - 261

NCS ensembles :
ID
1
2

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


Mass: 124464.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P42336, phosphatidylinositol 3-kinase, 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: 31537.439 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P27986
#3: Chemical ChemComp-A1CV8 / 2-({(1R)-1-[2-(1,3-dihydro-2H-isoindol-2-yl)-6-methyl-3-(oxan-4-yl)-4-oxo-3,4-dihydroquinazolin-8-yl]ethyl}amino)benzoic acid


Mass: 524.610 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H32N4O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-X3N / N~2~-{(4S,11aP)-2-[(4S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl}-L-alaninamide


Mass: 407.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19F2N5O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: 5.8 Å3/Da / Density % sol: 78.8 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1M MES pH6.50-6.80, 500mM Sodium chloride, 7-9% PEG3350
PH range: 6.5-6.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.03322 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 24, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03322 Å / Relative weight: 1
ReflectionResolution: 3.61→48.83 Å / Num. obs: 40827 / % possible obs: 99.2 % / Redundancy: 7.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.087 / Rpim(I) all: 0.053 / Rrim(I) all: 0.102 / Χ2: 1 / Net I/σ(I): 13.5
Reflection shellResolution: 3.61→3.76 Å / Rmerge(I) obs: 0.819 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 4593 / CC1/2: 0.833 / Rpim(I) all: 0.491 / Rrim(I) all: 0.957 / Χ2: 0.96 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.28data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.61→48.83 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.903 / SU B: 47.582 / SU ML: 0.703 / Cross valid method: THROUGHOUT / ESU R Free: 0.798 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29529 1949 4.8 %RANDOM
Rwork0.23959 ---
obs0.24238 38875 99.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 167.897 Å2
Baniso -1Baniso -2Baniso -3
1--0.86 Å2-0 Å2-4.28 Å2
2---7.34 Å20 Å2
3---8.41 Å2
Refinement stepCycle: 1 / Resolution: 3.61→48.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10448 0 68 0 10516
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01321435
X-RAY DIFFRACTIONr_bond_other_d0.0050.01520466
X-RAY DIFFRACTIONr_angle_refined_deg1.5381.6528933
X-RAY DIFFRACTIONr_angle_other_deg1.2251.58647185
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.29952520
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.4222.5941218
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.419154025
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.66115148
X-RAY DIFFRACTIONr_chiral_restr0.0710.22712
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0223894
X-RAY DIFFRACTIONr_gen_planes_other0.0020.025003
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_it7.6717.74210122
X-RAY DIFFRACTIONr_mcbond_other7.66917.74210121
X-RAY DIFFRACTIONr_mcangle_it12.75226.59912628
X-RAY DIFFRACTIONr_mcangle_other12.75226.612629
X-RAY DIFFRACTIONr_scbond_it6.43918.14111313
X-RAY DIFFRACTIONr_scbond_other6.43918.14111314
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other11.32827.0316306
X-RAY DIFFRACTIONr_long_range_B_refined20.42345138
X-RAY DIFFRACTIONr_long_range_B_other20.42345139
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.23 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A27917
12A27917
21C7200
22C7200
LS refinement shellResolution: 3.61→3.7 Å
RfactorNum. reflection% reflection
Rfree0.357 135 -
Rwork0.327 2865 -
obs--99.63 %

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