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- PDB-7r9v: Structure of PIK3CA with covalent inhibitor 19 -

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Basic information

Entry
Database: PDB / ID: 7r9v
TitleStructure of PIK3CA with covalent inhibitor 19
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 / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to L-leucine / response to butyrate / IRS-mediated signalling / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / autosome genomic imprinting ...response to muscle inactivity / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to L-leucine / response to butyrate / IRS-mediated signalling / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / autosome genomic imprinting / 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 / Signaling by LTK in cancer / anoikis / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by LTK / MET activates PI3K/AKT signaling / relaxation of cardiac muscle / 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 / PI-3K cascade:FGFR2 / response to dexamethasone / PI-3K cascade:FGFR4 / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / RET signaling / negative regulation of anoikis / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / PI3K events in ERBB2 signaling / insulin receptor substrate binding / intercalated disc / regulation of multicellular organism growth / CD28 dependent PI3K/Akt signaling / Role of LAT2/NTAL/LAB on calcium mobilization / RAC2 GTPase cycle / Interleukin receptor SHC signaling / positive regulation of TOR signaling / Role of phospholipids in phagocytosis / protein kinase activator activity / adipose tissue development / GAB1 signalosome / phagocytosis / endothelial cell migration / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Signaling by FGFR4 in disease / energy homeostasis / GPVI-mediated activation cascade / positive regulation of lamellipodium assembly / cardiac muscle contraction / 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 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / response to activity / Regulation of signaling by CBL / 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 / VEGFA-VEGFR2 Pathway / epidermal growth factor receptor signaling pathway / glucose metabolic process / cellular response to insulin stimulus / Signaling by CSF1 (M-CSF) in myeloid cells
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 / C2 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 / 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-2Q7 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.69 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 9, 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)110,8152
Polymers110,1991
Non-polymers6161
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 area36440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.060, 134.620, 144.580
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-2Q7 / 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]-1-(prop-2-enoyl)piperidine-4-carboxamide


Mass: 615.635 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H35F2N11O4 / 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: 2.61 Å3/Da / Density % sol: 52.83 %
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 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: 2.69→49.26 Å / Num. obs: 32779 / % possible obs: 99.68 % / Redundancy: 6.5 % / Biso Wilson estimate: 89.03 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.06991 / Rpim(I) all: 0.02972 / Rrim(I) all: 0.07611 / Net I/σ(I): 16.49
Reflection shellResolution: 2.69→2.786 Å / Redundancy: 6.4 % / Rmerge(I) obs: 2.373 / Mean I/σ(I) obs: 0.96 / Num. unique obs: 3221 / CC1/2: 0.465 / CC star: 0.797 / Rpim(I) all: 1.01 / % possible all: 99.47

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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: 2.69→49.26 Å / SU ML: 0.5608 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 37.2563
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2919 1634 4.99 %
Rwork0.2526 31091 -
obs0.2546 32725 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 114.06 Å2
Refinement stepCycle: LAST / Resolution: 2.69→49.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6587 0 44 0 6631
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00216786
X-RAY DIFFRACTIONf_angle_d0.45469242
X-RAY DIFFRACTIONf_chiral_restr0.03721042
X-RAY DIFFRACTIONf_plane_restr0.00331187
X-RAY DIFFRACTIONf_dihedral_angle_d11.52732411
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.69-2.770.51741320.49712496X-RAY DIFFRACTION99.39
2.77-2.860.47821330.43692568X-RAY DIFFRACTION99.63
2.86-2.960.43311350.38052555X-RAY DIFFRACTION99.41
2.96-3.080.3921340.35812542X-RAY DIFFRACTION99.63
3.08-3.220.39221360.36062567X-RAY DIFFRACTION99.85
3.22-3.390.32311340.29382560X-RAY DIFFRACTION99.67
3.39-3.60.30671360.27382584X-RAY DIFFRACTION99.82
3.6-3.880.30791360.24192585X-RAY DIFFRACTION99.93
3.88-4.270.27051370.2352598X-RAY DIFFRACTION99.93
4.27-4.890.25261360.20722621X-RAY DIFFRACTION99.93
4.89-6.150.26231390.23632637X-RAY DIFFRACTION99.71
6.16-49.260.26291460.22262778X-RAY DIFFRACTION99.56
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)
10.436305399229-0.3021875029670.3408237592120.253814252268-0.2691886128180.533905432156-0.315281345378-0.01750346465820.17284634325-0.03160010998080.3989028184680.2892786435660.2817791061320.5271325140436.19511694313E-60.8271618842690.0658364034510.1263321104490.7348840797470.1016512142431.0807934644914.7940458679-10.317506906133.4017415037
2-0.02814352119510.697832806327-0.0428088201061.058563628350.4796949650990.563094595979-0.225028752218-0.1324825919020.0923338010873-0.0485004753890.211477641754-0.5321671690370.007863907763050.129778170713-0.01765470916350.762855000291-0.04555757853040.06512017319810.6587844778440.009736073850050.769588005999.7517628218413.771708426930.7609611019
30.9268904865020.1732942405160.09826718183141.771947080860.1232826075891.25482938109-0.2118231716790.188310164691-0.393611618744-0.4065290756050.256939143491-0.6298101007330.02656364838630.1945048146450.002519595981790.763911268487-0.2117663828130.2564076510230.638897454536-0.1822942164010.56352324431612.3252425359-6.429442282074.8618194641
40.949342749091-0.843317805873-0.5160531691450.6578182316420.2376060662820.576271356997-0.0392289108031-0.28684353658-0.6440576030910.107377140035-0.114805211426-0.09892371975450.1851415456240.0164656414275-6.67428580382E-50.691509557074-0.07329937664880.08038709608290.692610870506-0.003346577078040.72846400336-2.95755088592-2.2620830483835.7263858001
50.966344641430.245602775740.5084992085310.1181238833190.02689834759650.3158073323390.0466902523554-0.1915344626260.05360143197650.0990834656011-0.1312024078610.200418609312-0.19323215238-0.3873880135031.87054648206E-50.730896459571-0.03870530230570.05595470810360.843786551512-0.01395702096330.766378475864-9.1068961168511.863038794831.588068901
60.327680024828-0.143255350127-0.2591394842790.104012441844-0.1382169911940.806529891751-0.1238307814870.5178387107960.2226940625870.06706013376170.3636444933890.6798044594320.042413983913-1.026337387251.34103238944E-60.7489731746780.0574766787132-0.004326887099541.101403020560.2360852562081.09487825031-20.829907104720.382990651521.7573434113
70.979721868310.6542696099090.3973413573561.32623685830.3700303988350.550697608453-0.3318445212150.737249812575-0.344734624552-0.7496524405890.630803727942-0.0504727427958-0.23513858735-0.1075664099930.02848913703381.00624446088-0.166356382784-0.2099798476450.9325007145840.1499382389390.505232036046-7.3111084497215.3398706885.84420607644
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 372 )155 - 37249 - 229
33chain 'A' and (resid 373 through 647 )373 - 647230 - 475
44chain 'A' and (resid 648 through 755 )648 - 755476 - 583
55chain 'A' and (resid 756 through 842 )756 - 842584 - 670
66chain 'A' and (resid 843 through 974 )843 - 974671 - 784
77chain 'A' and (resid 975 through 1045 )975 - 1045785 - 855

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