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- PDB-8twy: Structure of p110 alpha bound to (S)-1-(4-((2-(4-(4-(2-amino-4-(d... -

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Basic information

Entry
Database: PDB / ID: 8twy
TitleStructure of p110 alpha bound to (S)-1-(4-((2-(4-(4-(2-amino-4-(difluoromethyl)pyrimidin-5-yl)-6-(3-methylmorpholino)-1,3,5- triazin-2-yl)piperazin-1-yl)-2-oxoethoxy)methyl)piperidin-1-yl)prop-2-en-1-one (compound 9)
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE/Inhibitor / PI3K / PIK3CA / lipid kinase / TRANSFERASE / 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 / 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 / response to L-leucine / regulation of actin filament organization / 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 / positive regulation of protein localization to membrane / Activated NTRK2 signals through PI3K / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / 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 / 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 / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / relaxation of cardiac muscle / 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 / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / response to dexamethasone / negative regulation of anoikis / RET signaling / PI3K events in ERBB2 signaling / protein kinase activator activity / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / regulation of multicellular organism growth / intercalated disc / 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 / GAB1 signalosome / Role of phospholipids in phagocytosis / 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 / energy homeostasis / Signaling by FLT3 ITD and TKD mutants / cardiac muscle contraction / GPVI-mediated activation cascade / Signaling by FGFR3 in disease / Tie2 Signaling / Signaling by FGFR2 in disease / response to muscle stretch / T cell costimulation / RAC1 GTPase cycle / 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 / liver development / response to activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Regulation of signaling by CBL / positive regulation of smooth muscle cell proliferation / cellular response to glucose stimulus / 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 / 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, 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 ...PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding 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. / 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 / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.67 Å
AuthorsBurke, J.E. / Barlow-Busch, I.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)168998 Canada
CitationJournal: Chem Sci / Year: 2024
Title: Rapid, potent, and persistent covalent chemical probes to deconvolute PI3K alpha signaling.
Authors: Bissegger, L. / Constantin, T.A. / Keles, E. / Raguz, L. / Barlow-Busch, I. / Orbegozo, C. / Schaefer, T. / Borlandelli, V. / Bohnacker, T. / Sriramaratnam, R. / Schafer, A. / Gstaiger, M. / ...Authors: Bissegger, L. / Constantin, T.A. / Keles, E. / Raguz, L. / Barlow-Busch, I. / Orbegozo, C. / Schaefer, T. / Borlandelli, V. / Bohnacker, T. / Sriramaratnam, R. / Schafer, A. / Gstaiger, M. / Burke, J.E. / Borsari, C. / Wymann, M.P.
History
DepositionAug 21, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 20, 2024Group: Database references / Structure summary / Category: citation / citation_author / struct
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _struct.title
Revision 1.3Dec 4, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI ..._citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.4Dec 25, 2024Group: 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

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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)110,5872
Polymers109,9701
Non-polymers6171
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.130, 135.410, 143.710
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


Mass: 109970.156 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
#2: Chemical ChemComp-RNX / 1-(4-{[2-(4-{(4P)-4-[2-amino-4-(difluoromethyl)pyrimidin-5-yl]-6-[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl}piperazin-1-yl)-2-oxoethoxy]methyl}piperidin-1-yl)prop-2-en-1-one


Mass: 616.663 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H38F2N10O4 / 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: 52.98 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: PEG6000 10-15%, 0.6 M sodium formate, 0.1 M CHES pH 9.5-10.5, 5 mM TCEP
PH range: 9.5-10.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.95372 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Aug 9, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95372 Å / Relative weight: 1
ReflectionResolution: 2.67→49.7 Å / Num. obs: 33570 / % possible obs: 99.9 % / Redundancy: 13.5 % / CC1/2: 0.99 / Rmerge(I) obs: 0.113 / Net I/σ(I): 15.7
Reflection shellResolution: 2.67→2.73 Å / Rmerge(I) obs: 3.76 / Mean I/σ(I) obs: 0.77 / Num. unique obs: 2466 / CC1/2: 0.525 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.18.2_3874: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.67→49.7 Å / SU ML: 0.58 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 35.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2613 3776 5.99 %
Rwork0.2254 --
obs0.2276 33570 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.67→49.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6575 0 44 0 6619
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0046774
X-RAY DIFFRACTIONf_angle_d0.6719224
X-RAY DIFFRACTIONf_dihedral_angle_d12.4432406
X-RAY DIFFRACTIONf_chiral_restr0.041040
X-RAY DIFFRACTIONf_plane_restr0.0041183
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.67-2.70.49821330.50892117X-RAY DIFFRACTION97
2.7-2.740.46121600.48792192X-RAY DIFFRACTION99
2.74-2.780.39371130.41362245X-RAY DIFFRACTION100
2.78-2.820.47281260.40452209X-RAY DIFFRACTION100
2.82-2.860.42911630.38262152X-RAY DIFFRACTION100
2.86-2.90.49171330.35842190X-RAY DIFFRACTION100
2.9-2.950.36691390.33482249X-RAY DIFFRACTION100
2.95-30.34561290.3222178X-RAY DIFFRACTION100
3-3.060.33641590.31542161X-RAY DIFFRACTION100
3.06-3.110.3291290.3052253X-RAY DIFFRACTION100
3.12-3.180.34991300.29232142X-RAY DIFFRACTION100
3.18-3.250.31651490.27362240X-RAY DIFFRACTION100
3.25-3.320.30521360.27352212X-RAY DIFFRACTION100
3.32-3.410.32221390.29372160X-RAY DIFFRACTION100
3.41-3.50.3441470.25412225X-RAY DIFFRACTION100
3.5-3.60.34511440.23412188X-RAY DIFFRACTION100
3.6-3.720.28671350.21012216X-RAY DIFFRACTION100
3.72-3.850.22981410.21362176X-RAY DIFFRACTION100
3.85-40.22341330.20332213X-RAY DIFFRACTION100
4-4.190.23111440.19512197X-RAY DIFFRACTION100
4.19-4.410.22481450.18382181X-RAY DIFFRACTION100
4.41-4.680.22291380.17122221X-RAY DIFFRACTION100
4.68-5.040.22231390.17652208X-RAY DIFFRACTION100
5.04-5.550.2551480.20222197X-RAY DIFFRACTION100
5.55-6.350.25161400.23072198X-RAY DIFFRACTION100
6.35-80.22971310.222204X-RAY DIFFRACTION100
8-49.280.20821530.18842189X-RAY DIFFRACTION99
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)
12.93940.2997-0.60121.9652-0.0712.7466-0.1699-0.0727-0.27160.10570.2879-0.02040.62630.2029-0.13170.84460.03110.01380.73640.11521.207815.02-10.19833.398
22.5852-0.0537-0.5774.07091.042.69770.02860.18420.2124-0.0490.1829-0.2196-0.20990.0038-0.19460.8045-0.04570.02230.76630.08570.9229.24927.46838.897
31.09830.81860.25683.6410.70560.7616-0.26740.3878-0.5793-0.47940.3605-0.56610.24440.054-0.12520.8332-0.13960.18260.748-0.07920.78259.468-10.06913.65
41.36750.2821-0.01323.1940.1372.0656-0.16640.503-0.2757-0.83660.1336-0.5882-0.00010.30390.01290.917-0.21440.21450.8836-0.08450.838714.146-1.5555.271
53.6388-0.2646-1.03921.9550.5032.21650.0624-0.3142-0.41970.2461-0.16980.0760.1961-0.46830.08630.6612-0.08990.02680.69850.06640.7382-5.6641.39336.694
62.23690.6611-0.97951.95940.00641.6559-0.22070.41930.78530.15010.36910.36-0.2487-0.5454-0.12350.80680.065-0.0551.11750.16530.8829-15.64317.54324.027
73.449-0.9411-0.70842.53381.27162.96640.09151.06540.1205-0.6729-0.00260.8132-0.4744-0.9471-0.10780.883-0.0464-0.11481.23140.28170.819-12.6318.1411.712
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 107:154 )A107 - 154
2X-RAY DIFFRACTION2( CHAIN A AND RESID 155:266 )A155 - 266
3X-RAY DIFFRACTION3( CHAIN A AND RESID 267:438 )A267 - 438
4X-RAY DIFFRACTION4( CHAIN A AND RESID 439:647 )A439 - 647
5X-RAY DIFFRACTION5( CHAIN A AND RESID 648:807 )A648 - 807
6X-RAY DIFFRACTION6( CHAIN A AND RESID 808:886 )A808 - 886
7X-RAY DIFFRACTION7( CHAIN A AND RESID 887:1045 )A887 - 1045

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