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- PDB-7r9y: Structure of PIK3CA with covalent inhibitor 22 -

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Basic information

Entry
Database: PDB / ID: 7r9y
TitleStructure of PIK3CA with covalent inhibitor 22
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PI3K / p110 / PIK3CA / PIP3 / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of actin filament organization / response to L-leucine / response to butyrate / IRS-mediated signalling / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure ...response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of actin filament organization / response to L-leucine / response to butyrate / IRS-mediated signalling / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / regulation of cellular respiration / Activated NTRK2 signals through PI3K / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / positive regulation of protein localization to membrane / vasculature development / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by cytosolic FGFR1 fusion mutants / Co-stimulation by ICOS / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / Nephrin family interactions / anoikis / Signaling by LTK in cancer / phosphatidylinositol-3-phosphate biosynthetic process / relaxation of cardiac muscle / Signaling by LTK / MET activates PI3K/AKT signaling / PI3K/AKT activation / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of macroautophagy / response to dexamethasone / PI-3K cascade:FGFR2 / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / energy homeostasis / RET signaling / negative regulation of anoikis / PI3K events in ERBB2 signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / intercalated disc / protein kinase activator activity / regulation of multicellular organism growth / CD28 dependent PI3K/Akt signaling / positive regulation of TOR signaling / Role of LAT2/NTAL/LAB on calcium mobilization / RAC2 GTPase cycle / Interleukin receptor SHC signaling / Role of phospholipids in phagocytosis / GAB1 signalosome / adipose tissue development / phagocytosis / endothelial cell migration / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Signaling by FGFR4 in disease / positive regulation of lamellipodium assembly / cardiac muscle contraction / GPVI-mediated activation cascade / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR3 in disease / Tie2 Signaling / response to muscle stretch / Signaling by FGFR2 in disease / RAC1 GTPase cycle / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / positive regulation of smooth muscle cell proliferation / Downstream signal transduction / insulin-like growth factor receptor signaling pathway / Regulation of signaling by CBL / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / response to activity / cellular response to glucose stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / liver development / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / platelet activation / Signaling by CSF1 (M-CSF) in myeloid cells / VEGFA-VEGFR2 Pathway / epidermal growth factor receptor signaling pathway / cellular response to insulin stimulus / glucose metabolic process
Similarity search - Function
PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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. ...PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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 / 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. / C2 domain / 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-2IX / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsBurke, J.E. / McPhail, J.A.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)168998 Canada
CitationJournal: J.Am.Chem.Soc. / Year: 2022
Title: Covalent Proximity Scanning of a Distal Cysteine to Target PI3K alpha.
Authors: Borsari, C. / Keles, E. / McPhail, J.A. / Schaefer, A. / Sriramaratnam, R. / Goch, W. / Schaefer, T. / De Pascale, M. / Bal, W. / Gstaiger, M. / Burke, J.E. / Wymann, M.P.
History
DepositionJun 29, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)110,8292
Polymers110,1991
Non-polymers6301
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area36270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.100, 134.410, 145.300
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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: 110199.398 Da / Num. of mol.: 1
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-2IX / N-[2-(4-{4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-yl}piperazin-1-yl)-2-oxoethyl]-N-methyl-1-(prop-2-enoyl)piperidine-4-carboxamide


Mass: 629.661 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H37F2N11O4 / 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: 2.62 Å3/Da / Density % sol: 53.03 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: PEG6000 8%, 0.6 M sodium formate, 0.1 M CHES pH 9.4, 5 mM TCEP
PH range: 9.1 - 9.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9786 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 17, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.85→45.57 Å / Num. obs: 27775 / % possible obs: 97.55 % / Redundancy: 6.5 % / Biso Wilson estimate: 90.71 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.06181 / Rpim(I) all: 0.0263 / Rrim(I) all: 0.06731 / Net I/σ(I): 19.26
Reflection shellResolution: 2.85→2.952 Å / Redundancy: 6.6 % / Rmerge(I) obs: 1.348 / Mean I/σ(I) obs: 1.82 / Num. unique obs: 2731 / CC1/2: 0.793 / CC star: 0.941 / Rpim(I) all: 0.5617 / % possible all: 96.4

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4TUU

4tuu


Resolution: 2.85→45.57 Å / SU ML: 0.5832 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 36.6612
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2875 1357 5 %
Rwork0.2473 25785 -
obs0.2493 27142 97.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 109.05 Å2
Refinement stepCycle: LAST / Resolution: 2.85→45.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6575 0 45 0 6620
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00176775
X-RAY DIFFRACTIONf_angle_d0.44249226
X-RAY DIFFRACTIONf_chiral_restr0.03691039
X-RAY DIFFRACTIONf_plane_restr0.00291184
X-RAY DIFFRACTIONf_dihedral_angle_d10.4122408
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.85-2.950.48161320.42522518X-RAY DIFFRACTION96.43
2.95-3.070.42691340.40332545X-RAY DIFFRACTION98.75
3.07-3.210.43711350.39282563X-RAY DIFFRACTION98.79
3.21-3.380.38841340.31012564X-RAY DIFFRACTION98.47
3.38-3.590.2891360.27592572X-RAY DIFFRACTION98.22
3.59-3.870.28351360.25382579X-RAY DIFFRACTION98.48
3.87-4.260.27941360.22352593X-RAY DIFFRACTION97.92
4.26-4.870.23331360.19842579X-RAY DIFFRACTION97.28
4.87-6.130.2471360.23172594X-RAY DIFFRACTION96.98
6.14-45.570.27741420.21862678X-RAY DIFFRACTION94.82
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)
13.06364243032-0.4318421457-0.524511168071.92640117491-0.1335758679642.14740490576-0.252273771942-0.4297791013160.06571489940830.1193466402310.425791487444-0.04024318854850.4317934034750.332462727767-0.2089309027930.7579946910910.05269878319990.06640289651480.6623246358450.131730316071.0930594548214.7936104685-10.455941910133.4957524204
22.606576196760.0384183224839-0.3433596577582.54986694531.109133346111.72475239134-0.06487688917190.003739546416260.1694158540140.1630235616070.08721754984430.026091561828-0.147343882370.122055283852-0.0002061300088420.682456531817-0.0576342386161-0.00306371138510.6371450735930.03564978594380.6717764574979.0658979704424.760313810139.5113513509
31.443129655420.444855757756-0.2304036187693.30418514832-0.03960085652491.44745581469-0.2324273611150.0968377396632-0.394387288381-0.668672323360.203621046644-0.628765213870.1488546097540.1379007727280.02163904630260.858808436785-0.1335836135960.2146789066090.65058958023-0.1371680222670.69921064097412.2078815578-8.59879663014.9733086385
43.22553510855-0.892308117539-1.137997529531.554115181610.3083325317591.88435521497-0.070789462817-0.266860037126-0.5012707382730.294754629173-0.0358435235412-0.01107010274980.24767781318-0.08500184080370.1610987282040.540545894969-0.05495930634840.03775119071350.5300537231680.03061663183910.594955003208-2.97727738702-2.4381433797335.871149174
51.030713177160.2437997818030.6404707910910.675629293987-0.6266502405562.34161019016-0.0152681550585-0.187328100375-0.08514753621360.146500904253-0.1418181852570.179926557109-0.111351334021-0.5657579163480.1593508039620.651426299566-0.01170327261110.08765187016810.814937041312-0.1205132472690.850897838809-9.1527254663211.679648796331.7828998648
61.796332027640.463258504438-0.3181084308551.48885177499-0.5182455102521.43429600766-0.04208150399830.3263901985480.8448518896180.08106354068320.2335398629760.903278106537-0.147260906761-0.571199590543-0.2514061939390.7414296113320.05093563970320.03792365077390.9220707982210.1554844970631.1833378977-20.902170316220.275543137322.1022373103
73.04442880767-0.2245644926620.9780658428942.81730750112-0.54519721721.74956920431-0.4517710311151.09079604721-0.416481519405-1.18638516520.7574559448160.368914355909-0.190909542988-0.153795456058-0.2153442474980.977582697477-0.139650796472-0.2113777874641.047431724960.09068327901890.579191736903-7.3436016453415.26862799156.03875075852
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 107 through 154 )107 - 1541 - 48
22chain 'A' and (resid 155 through 304 )155 - 30449 - 183
33chain 'A' and (resid 305 through 647 )305 - 647184 - 474
44chain 'A' and (resid 648 through 755 )648 - 755475 - 582
55chain 'A' and (resid 756 through 842 )756 - 842583 - 669
66chain 'A' and (resid 843 through 974 )843 - 974670 - 782
77chain 'A' and (resid 975 through 1045 )975 - 1045783 - 853

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