[English] 日本語
Yorodumi
- PDB-8exv: Crystal structure of PI3K-alpha in complex with compound 32 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8exv
TitleCrystal structure of PI3K-alpha in complex with compound 32
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsCELL CYCLE / PI3K / drug / inhibitor / cancer / oncology
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 / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K ...response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IB / vasculature development / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / phosphatidylinositol 3-kinase complex / anoikis / Nephrin family interactions / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Costimulation by the CD28 family / vascular endothelial growth factor signaling pathway / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / MET activates PI3K/AKT signaling / PI3K/AKT activation / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase / relaxation of cardiac muscle / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / negative regulation of macroautophagy / Signaling by ALK / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / response to dexamethasone / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / PI3K events in ERBB2 signaling / Signaling by ALK fusions and activated point mutants / negative regulation of anoikis / RET signaling / regulation of multicellular organism growth / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / intercalated disc / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / GAB1 signalosome / Role of phospholipids in phagocytosis / Role of LAT2/NTAL/LAB on calcium mobilization / adipose tissue development / Interleukin receptor SHC signaling / positive regulation of lamellipodium assembly / phagocytosis / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / energy homeostasis / Signaling by FGFR4 in disease / Signaling by FLT3 ITD and TKD mutants / cardiac muscle contraction / Signaling by FGFR3 in disease / GPVI-mediated activation cascade / Tie2 Signaling / Signaling by FGFR2 in disease / RAC1 GTPase cycle / T cell costimulation / response to muscle stretch / 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 / response to activity / liver development / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Regulation of signaling by CBL / cellular response to glucose stimulus / positive regulation of smooth muscle cell proliferation / regulation of protein phosphorylation / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / platelet activation / VEGFA-VEGFR2 Pathway / cellular response to insulin stimulus / glucose metabolic process / Constitutive Signaling by Aberrant PI3K in Cancer
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. / Phosphoinositide 3-kinase C2 ...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. / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain / C2 phosphatidylinositol 3-kinase-type domain / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK 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 / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-X3N / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsKiefer, J.R. / Eigenbrot, C. / Staben, S.T. / Hanan, E.J. / Wallweber, H.J.A. / Ultsch, M. / Braun, M.G. / Friedman, L.S. / Purkey, H.E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3K alpha.
Authors: Hanan, E.J. / Braun, M.G. / Heald, R.A. / MacLeod, C. / Chan, C. / Clausen, S. / Edgar, K.A. / Eigenbrot, C. / Elliott, R. / Endres, N. / Friedman, L.S. / Gogol, E. / Gu, X.H. / Thibodeau, R. ...Authors: Hanan, E.J. / Braun, M.G. / Heald, R.A. / MacLeod, C. / Chan, C. / Clausen, S. / Edgar, K.A. / Eigenbrot, C. / Elliott, R. / Endres, N. / Friedman, L.S. / Gogol, E. / Gu, X.H. / Thibodeau, R.H. / Jackson, P.S. / Kiefer, J.R. / Knight, J.D. / Nannini, M. / Narukulla, R. / Pace, A. / Pang, J. / Purkey, H.E. / Salphati, L. / Sampath, D. / Schmidt, S. / Sideris, S. / Song, K. / Sujatha-Bhaskar, S. / Ultsch, M. / Wallweber, H. / Xin, J. / Yeap, S. / Young, A. / Zhong, Y. / Staben, S.T.
History
DepositionOct 25, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 30, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 14, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 4, 2023Group: 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)126,3592
Polymers125,9511
Non-polymers4071
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.720, 133.720, 141.740
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

-
Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform / PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / ...PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / PtdIns-3-kinase subunit p110-alpha / p110alpha / Phosphoinositide 3-kinase alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 125951.273 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 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-X3N / N~2~-{(4S,11aP)-2-[(4S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl}-L-alaninamide


Mass: 407.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19F2N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 71 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.21 Å3/Da / Density % sol: 44.32 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.2 / Details: 0.1M MES buffer pH 6.2, 16% PEG 20,000, 0.1M KCl

-
Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.48→50 Å / Num. obs: 38159 / % possible obs: 95.1 % / Redundancy: 6.1 % / Biso Wilson estimate: 59.74 Å2 / Rmerge(I) obs: 0.086 / Rpim(I) all: 0.038 / Rrim(I) all: 0.095 / Χ2: 0.958 / Net I/σ(I): 8.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.5-2.595.90.8339480.810.370.9110.93299.9
2.59-2.695.80.63739540.8630.2860.70.96899.7
2.69-2.825.40.46238950.8950.2180.5130.95799.1
2.82-2.966.10.29339510.9660.1290.320.972100
2.96-3.156.50.19539640.9810.0830.2130.963100
3.15-3.396.50.13339750.9910.0560.1440.955100
3.39-3.736.30.10127800.9940.0430.110.95669.4
3.73-4.275.50.06733930.9950.0310.0740.96184.4
4.27-5.386.80.04940780.9980.020.0530.901100
5.38-506.20.04242210.9980.0180.0461.01698.9

-
Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER2.11.6refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NULL

Resolution: 2.48→48.63 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.906 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.509 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.502 / SU Rfree Blow DPI: 0.286 / SU Rfree Cruickshank DPI: 0.291
RfactorNum. reflection% reflectionSelection details
Rfree0.258 943 2.51 %RANDOM
Rwork0.205 ---
obs0.207 37522 92.9 %-
Displacement parametersBiso max: 186.89 Å2 / Biso mean: 60.62 Å2 / Biso min: 25.56 Å2
Baniso -1Baniso -2Baniso -3
1-2.983 Å20 Å20 Å2
2---9.826 Å20 Å2
3---6.843 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 2.48→48.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7325 0 31 71 7427
Biso mean--44.45 51.33 -
Num. residues----895
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2707SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes206HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1059HARMONIC5
X-RAY DIFFRACTIONt_it7547HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion952SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8329SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7547HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg10202HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion2.73
X-RAY DIFFRACTIONt_other_torsion18.31
LS refinement shellResolution: 2.48→2.55 Å / Rfactor Rfree error: 0 / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.315 78 2.85 %
Rwork0.215 2659 -
all0.217 2737 -
obs--88.55 %
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)
12.611-1.3291-0.72822.15330.50372.7912-0.1475-0.5081-0.08270.31270.1692-0.25770.34070.5435-0.0217-0.12550.0809-0.05860.07760.0005-0.163416.808-5.191336.0594
22.1206-0.5005-0.44138.31552.89861.1803-0.09420.0120.3296-0.4830.4148-0.458-0.50930.1625-0.32060.0654-0.05930.0696-0.2176-0.0986-0.16318.654230.284939.0439
31.9561.8032-1.06743.1061-0.75443.8482-0.15310.2616-0.1755-0.32790.20.10240.5442-0.1419-0.04690.0658-0.02290.0256-0.2406-0.0371-0.14788.3482-19.95513.9045
40.8055-0.1111-0.8640.30470.02932.87810.06710.07410.0547-0.05250.048-0.0521-0.210.274-0.1151-0.0874-0.02520.01390.0118-0.0565-0.072216.24234.33877.094
53.3892-0.4590.09451.60820.07082.57150.1772-0.2491-0.11930.0403-0.01620.325-0.1454-0.5442-0.161-0.1540.0370.02910.09230.0112-0.1342-11.6664.663440.9378
61.766-0.81520.48583.2626-0.54972.4949-0.0317-0.00010.21640.02950.0988-0.1296-0.3609-0.1842-0.0672-0.05390.0822-0.01760.0085-0.0535-0.0864-6.038914.723722.2905
72.424-0.4738-0.42232.8194-0.0762.7139-0.09320.34190.3354-0.20370.1640.3811-0.5442-0.5422-0.0708-0.15360.093-0.053-0.02390.0803-0.1476-14.891621.547712.2998
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|107 - A|167 A|298 - A|310 }A107 - 167
2X-RAY DIFFRACTION1{ A|107 - A|167 A|298 - A|310 }A298 - 310
3X-RAY DIFFRACTION2{ A|168 - A|297 }A168 - 297
4X-RAY DIFFRACTION3{ A|322 - A|489 }A322 - 489
5X-RAY DIFFRACTION4{ A|490 - A|695 }A490 - 695
6X-RAY DIFFRACTION5{ A|696 - A|804 }A696 - 804
7X-RAY DIFFRACTION6{ A|805 - A|853 }A805 - 853
8X-RAY DIFFRACTION7{ A|854 - A|1051 }A854 - 1051

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more