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- PDB-7tz7: PI3K alpha in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 7tz7
TitlePI3K alpha in complex with an inhibitor
Components
  • Isoform 3 of Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Keywordstransferase/inhibitor / Inhibitor / heterodimer / transferase / transferase-inhibitor complex
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling / positive regulation of focal adhesion disassembly / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase activator activity / autosome genomic imprinting / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulatory subunit binding / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / positive regulation of endoplasmic reticulum unfolded protein response / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / cis-Golgi network / ErbB-3 class receptor binding / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / regulation of cellular respiration / RHOF GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / RHOD GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / enzyme-substrate adaptor activity / Nephrin family interactions / anoikis / Signaling by LTK in cancer / Costimulation by the CD28 family / RND1 GTPase cycle / Signaling by LTK / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / relaxation of cardiac muscle / MET activates PI3K/AKT signaling / positive regulation of leukocyte migration / PI3K/AKT activation / RND2 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of filopodium assembly / RND3 GTPase cycle / growth hormone receptor signaling pathway / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / negative regulation of stress fiber assembly / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / natural killer cell mediated cytotoxicity / 1-phosphatidylinositol-3-kinase activity / RHOV GTPase cycle / negative regulation of cell-matrix adhesion / Signaling by ALK / negative regulation of macroautophagy / RHOB GTPase cycle / GP1b-IX-V activation signalling / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / PI-3K cascade:FGFR4 / response to dexamethasone / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / negative regulation of osteoclast differentiation / intracellular glucose homeostasis / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / RHOU GTPase cycle / CDC42 GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / PI3K Cascade / RET signaling / intercalated disc / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / T cell differentiation / RHOG GTPase cycle / regulation of multicellular organism growth / extrinsic apoptotic signaling pathway via death domain receptors / endothelial cell migration / positive regulation of TOR signaling / RHOA GTPase cycle
Similarity search - Function
PI3Kalpha, catalytic 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 / 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 ...PI3Kalpha, catalytic 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 / 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. / 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 / Rho GTPase activation protein / 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- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / 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-KVJ / 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: 2.41 Å
AuthorsKnapp, M.S. / Tang, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor.
Authors: Fairhurst, R.A. / Furet, P. / Imbach-Weese, P. / Stauffer, F. / Rueeger, H. / McCarthy, C. / Ripoche, S. / Oswald, S. / Arnaud, B. / Jary, A. / Maira, M. / Schnell, C. / Guthy, D.A. / ...Authors: Fairhurst, R.A. / Furet, P. / Imbach-Weese, P. / Stauffer, F. / Rueeger, H. / McCarthy, C. / Ripoche, S. / Oswald, S. / Arnaud, B. / Jary, A. / Maira, M. / Schnell, C. / Guthy, D.A. / Wartmann, M. / Kiffe, M. / Desrayaud, S. / Blasco, F. / Widmer, T. / Seiler, F. / Gutmann, S. / Knapp, M. / Caravatti, G.
History
DepositionFeb 15, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 6, 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

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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: Isoform 3 of Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,6283
Polymers160,1722
Non-polymers4551
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6210 Å2
ΔGint-17 kcal/mol
Surface area52810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.870, 109.672, 135.242
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
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: 125287.828 Da / Num. of mol.: 1 / Mutation: M232K, L233K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Baculoviridae sp. (virus)
References: UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Protein Isoform 3 of 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: 34884.391 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: unidentified baculovirus / References: UniProt: P27986
#3: Chemical ChemComp-KVJ / (4S,5R)-3-[2'-amino-2-(morpholin-4-yl)-4'-(trifluoromethyl)[4,5'-bipyrimidin]-6-yl]-4-(hydroxymethyl)-5-methyl-1,3-oxazolidin-2-one


Mass: 455.391 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20F3N7O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.31 Å3/Da / Density % sol: 46.85 %
Crystal growTemperature: 303.15 K / Method: vapor diffusion, hanging drop / Details: 0.15M Potassium Thiocyanate, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9774 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.41→64.81 Å / Num. obs: 57881 / % possible obs: 100 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 6.7 % / Biso Wilson estimate: 65.22 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.037 / Rrim(I) all: 0.097 / Net I/σ(I): 11.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.41-2.546.92.1750.983430.4410.8932.354100
7.63-64.815.80.02720120.9990.0120.0399.7

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Processing

Software
NameVersionClassification
PHENIX1.19.2-4158-000refinement
XDS1.1.7data reduction
Aimlessdata scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4JPS

4jps


Resolution: 2.41→54.84 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 33.82 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2773 2809 4.87 %Random
Rwork0.2389 54855 --
obs0.2409 57664 99.72 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 197.72 Å2 / Biso mean: 90.6423 Å2 / Biso min: 38.67 Å2
Refinement stepCycle: final / Resolution: 2.41→54.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9939 0 32 31 10002
Biso mean--75.34 62.9 -
Num. residues----1254
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.41-2.450.40431410.37962624276597
2.45-2.50.40181400.36722683282399
2.5-2.550.38271170.354927322849100
2.55-2.60.46181420.361627042846100
2.6-2.660.40251370.381727092846100
2.66-2.720.33751190.345527452864100
2.72-2.790.36611280.31927222850100
2.79-2.860.34681520.312827202872100
2.86-2.940.33381280.29527402868100
2.94-3.040.34221580.293227162874100
3.04-3.150.31911490.300927052854100
3.15-3.270.37621380.307227152853100
3.27-3.420.33631700.279827282898100
3.42-3.60.28331290.254927532882100
3.6-3.830.26821500.235227452895100
3.83-4.130.28111430.22127692912100
4.13-4.540.24521460.194127792925100
4.54-5.20.21921300.184727902920100
5.2-6.550.27121370.222628342971100
6.55-54.840.20151550.18729423097100
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)
15.54850.0785-1.63283.33580.79023.8779-0.0031-0.55870.43920.26910.1223-0.2720.15260.5597-0.07140.4246-0.0258-0.05280.5598-0.020.428324.220335.3997-38.726
20.9273-0.3553-0.62690.26880.29671.2480.2403-0.56811.17940.8816-0.29210.3027-0.44130.1076-0.20361.3652-0.55210.39920.978-0.65860.7874-6.560839.8701-12.7201
32.17160.2199-0.24380.91970.23152.1820.4101-0.39820.87610.392-0.13720.3176-0.28840.3588-0.17510.9351-0.41170.3650.7141-0.30250.9363-9.622336.2132-27.5551
43.31220.9448-0.64641.6446-0.35762.36820.16050.37580.91040.05830.16270.6193-0.4013-0.2393-0.23450.47110.01990.13010.40460.10110.7359-20.857532.8413-41.0877
52.00570.8376-0.41982.2824-0.83631.88240.4473-1.3706-0.34260.6634-0.452-0.4930.00731.01770.010.626-0.1221-0.11321.15880.07470.466-1.904514.2541-15.5175
63.70570.9775-0.36763.5085-2.44384.04390.387-0.6029-0.29040.3053-0.06950.42230.2047-0.154-0.32720.4544-0.03960.08670.55570.06040.4961-23.20198.5469-19.4767
77.2121-0.5527-2.20382.22390.17972.8194-0.74530.4075-1.34670.17790.07420.69330.5913-0.31650.60920.6844-0.05910.25770.9320.09191.2642-45.268614.4495-43.0194
88.0769-2.636-3.32770.98660.48144.5859-0.10921.176-0.4993-0.1422-0.62281.24320.002-1.30920.33550.6665-0.17590.06281.4246-0.23211.1732-49.61918.5992-51.7708
90.20660.8916-1.05944.9707-5.76286.69131.2907-0.5366-0.95811.2706-0.9131.7071-0.3068-0.1675-0.2111.4634-0.121-0.49141.28230.15791.2053-35.0588-5.104-50.9496
104.146.0681-0.86978.9299-1.99281.9414-0.05460.6513-0.5480.13580.3302-0.29240.1042-0.0268-0.21110.36950.034-0.00160.4274-0.08650.50772.606115.9516-49.3398
118.5815.2933-1.02214.5728-1.28211.2514-0.17421.2018-0.9633-0.05330.3985-0.5924-0.01750.0803-0.11340.5112-0.01330.06010.6254-0.15090.44327.549318.2198-52.7718
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 121 )A2 - 121
2X-RAY DIFFRACTION2chain 'A' and (resid 122 through 227 )A122 - 227
3X-RAY DIFFRACTION3chain 'A' and (resid 228 through 352 )A228 - 352
4X-RAY DIFFRACTION4chain 'A' and (resid 353 through 720 )A353 - 720
5X-RAY DIFFRACTION5chain 'A' and (resid 721 through 911 )A721 - 911
6X-RAY DIFFRACTION6chain 'A' and (resid 912 through 1052 )A912 - 1052
7X-RAY DIFFRACTION7chain 'B' and (resid 326 through 400 )B326 - 400
8X-RAY DIFFRACTION8chain 'B' and (resid 401 through 429 )B401 - 429
9X-RAY DIFFRACTION9chain 'B' and (resid 430 through 441 )B430 - 441
10X-RAY DIFFRACTION10chain 'B' and (resid 442 through 506 )B442 - 506
11X-RAY DIFFRACTION11chain 'B' and (resid 507 through 591 )B507 - 591

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