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- PDB-5xgi: Crystal structure of PI3K complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 5xgi
TitleCrystal structure of PI3K complex with an inhibitor
Components(Phosphatidylinositol ...) x 2
KeywordsTRANSFERASE/INHIBITOR / PI3K / inhibitor / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / phosphatidylinositol kinase activity / phosphatidylinositol 3-kinase regulator activity / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / regulation of actin filament organization / negative regulation of actin filament depolymerization / phosphatidylinositol 3-kinase activator activity ...perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / phosphatidylinositol kinase activity / phosphatidylinositol 3-kinase regulator activity / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / regulation of actin filament organization / negative regulation of actin filament depolymerization / phosphatidylinositol 3-kinase activator activity / response to butyrate / T follicular helper cell differentiation / IRS-mediated signalling / response to L-leucine / interleukin-18-mediated signaling pathway / phosphatidylinositol 3-kinase regulatory subunit binding / myeloid leukocyte migration / PI3K events in ERBB4 signaling / neurotrophin TRKA receptor binding / positive regulation of focal adhesion disassembly / cellular response to hydrostatic pressure / autosome genomic imprinting / cis-Golgi network / Activated NTRK2 signals through PI3K / ErbB-3 class receptor binding / transmembrane receptor protein tyrosine kinase adaptor activity / negative regulation of fibroblast apoptotic process / 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 / Signaling by cytosolic FGFR1 fusion mutants / RHOD GTPase cycle / positive regulation of protein localization to membrane / vasculature development / regulation of cellular respiration / Nephrin family interactions / RHOF GTPase cycle / kinase activator activity / Signaling by LTK in cancer / positive regulation of leukocyte migration / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by LTK / anoikis / RND1 GTPase cycle / RND2 GTPase cycle / relaxation of cardiac muscle / positive regulation of filopodium assembly / RND3 GTPase cycle / phosphatidylinositol 3-kinase complex, class IA / PI3K/AKT activation / MET activates PI3K/AKT signaling / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / growth hormone receptor signaling pathway / phosphatidylinositol 3-kinase / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by ALK / RHOV GTPase cycle / cardiac muscle cell contraction / 1-phosphatidylinositol-3-kinase activity / vascular endothelial growth factor signaling pathway / RHOB GTPase cycle / natural killer cell mediated cytotoxicity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / response to dexamethasone / PI-3K cascade:FGFR2 / negative regulation of macroautophagy / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / negative regulation of osteoclast differentiation / phosphatidylinositol phosphate biosynthetic process / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / RHOU GTPase cycle / CDC42 GTPase cycle / RET signaling / negative regulation of anoikis / T cell differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / RHOG GTPase cycle / PI3K events in ERBB2 signaling / PI3K Cascade / negative regulation of cell-matrix adhesion / intercalated disc / extrinsic apoptotic signaling pathway via death domain receptors / RHOA GTPase cycle / Role of LAT2/NTAL/LAB on calcium mobilization / RAC3 GTPase cycle / CD28 dependent PI3K/Akt signaling / RAC2 GTPase cycle / regulation of multicellular organism growth
Similarity search - Function
Helix Hairpins - #1490 / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3Kalpha, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain ...Helix Hairpins - #1490 / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3Kalpha, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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 domain / 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 / SH2 domain / SHC Adaptor Protein / 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Src homology 3 (SH3) domain profile. / SH3 domain / Helix Hairpins / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-84R / 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: 2.56 Å
AuthorsSong, K. / Yang, X. / Zhao, Y. / Jian, Z.
CitationJournal: To Be Published
Title: Crystal structure of PI3K complex with an inhibitor
Authors: Song, K. / Yang, X. / Zhao, Y. / Jian, Z.
History
DepositionApr 13, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 25, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.d_res_low

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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)157,2249
Polymers156,1412
Non-polymers1,0837
Water1,838102
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8700 Å2
ΔGint-63 kcal/mol
Surface area57480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.348, 135.825, 150.245
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Phosphatidylinositol ... , 2 types, 2 molecules AB

#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: 122644.914 Da / Num. of mol.: 1 / Fragment: UNP residues 8-1059
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: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit ...PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 33495.809 Da / Num. of mol.: 1 / Fragment: UNP residues 322-598
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27986

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Non-polymers , 5 types, 109 molecules

#3: Chemical ChemComp-84R / 3-azanyl-5-(4-morpholin-4-ylthieno[3,2-d]pyrimidin-2-yl)phenol


Mass: 328.389 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16N4O2S
#4: Chemical ChemComp-P6G / HEXAETHYLENE GLYCOL / POLYETHYLENE GLYCOL PEG400


Mass: 282.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H26O7 / Comment: precipitant*YM
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 102 / 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: 2.4 Å3/Da / Density % sol: 48.69 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop
Details: 0.15M Lithium sulfate, 0.1M Tris-HCl pH 8.5, 28%(W/V) PEG2000MME

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: CMOS / Date: Apr 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.56→50 Å / Num. obs: 47786 / % possible obs: 99.8 % / Redundancy: 6.5 % / Net I/σ(I): 12.71
Reflection shellResolution: 2.56→2.65 Å / Redundancy: 6.2 % / Mean I/σ(I) obs: 2.17 / Num. unique obs: 4675 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data processing
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.56→50 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.907 / SU B: 14.892 / SU ML: 0.317 / Cross valid method: THROUGHOUT / ESU R: 1.423 / ESU R Free: 0.37 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29043 2366 5 %RANDOM
Rwork0.23947 ---
obs0.24202 45351 99.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 76.637 Å2
Baniso -1Baniso -2Baniso -3
1-1.62 Å2-0 Å2-0 Å2
2---4.58 Å20 Å2
3---2.96 Å2
Refinement stepCycle: 1 / Resolution: 2.56→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10647 0 69 102 10818
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01910938
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210517
X-RAY DIFFRACTIONr_angle_refined_deg1.0361.96814743
X-RAY DIFFRACTIONr_angle_other_deg0.85324224
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.41351283
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.96924.353549
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.401152063
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.9721576
X-RAY DIFFRACTIONr_chiral_restr0.0570.21589
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212148
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022537
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_it1.7737.6085153
X-RAY DIFFRACTIONr_mcbond_other1.7737.6085152
X-RAY DIFFRACTIONr_mcangle_it3.13511.4026429
X-RAY DIFFRACTIONr_mcangle_other3.13511.4036430
X-RAY DIFFRACTIONr_scbond_it1.4227.7865785
X-RAY DIFFRACTIONr_scbond_other1.4227.7865785
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.55611.5818315
X-RAY DIFFRACTIONr_long_range_B_refined5.40658.81912116
X-RAY DIFFRACTIONr_long_range_B_other5.40558.82112117
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.556→2.622 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.392 156 -
Rwork0.33 3043 -
obs--92.51 %

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