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- PDB-6gvi: Crystal structure of PI3K alpha in complex with 3-(2-Amino-benzoo... -

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Entry
Database: PDB / ID: 6gvi
TitleCrystal structure of PI3K alpha in complex with 3-(2-Amino-benzooxazol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE / LIPID KINASE / INHIBITOR / PI3K ALPHA / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX / TRANSFERASE-TRANSFERASE REGULATOR 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 / 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, class IA / anoikis / phosphatidylinositol 3-kinase complex / Nephrin family interactions / Costimulation by the CD28 family / relaxation of cardiac muscle / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / MET activates PI3K/AKT signaling / PI3K/AKT activation / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / negative regulation of macroautophagy / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / response to dexamethasone / PI-3K cascade:FGFR2 / protein kinase activator activity / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / PI3K events in ERBB2 signaling / negative regulation of anoikis / intercalated disc / RET signaling / regulation of multicellular organism growth / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / Role of phospholipids in phagocytosis / GAB1 signalosome / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / adipose tissue development / phagocytosis / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / energy homeostasis / positive regulation of lamellipodium assembly / Signaling by FGFR4 in disease / cardiac muscle contraction / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR3 in disease / Tie2 Signaling / GPVI-mediated activation cascade / Signaling by FGFR2 in disease / T cell costimulation / RAC1 GTPase cycle / response to muscle stretch / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Downstream signal transduction / phosphatidylinositol 3-kinase/protein kinase B signal transduction / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / liver development / response to activity / 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 / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / 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-FDW / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsOuvry, G. / Aurelly, M. / Bonnary, L. / Borde, E. / Bouix-Peter, C. / Chantalat, L. / Clary, L. / Defoin-Platel, C. / Deret, S. / Forissier, M. ...Ouvry, G. / Aurelly, M. / Bonnary, L. / Borde, E. / Bouix-Peter, C. / Chantalat, L. / Clary, L. / Defoin-Platel, C. / Deret, S. / Forissier, M. / Harris, C.S. / Isabet, T. / Lamy, L. / Luzy, A.P. / Pascau, J. / Soulet, C. / Taddei, A. / Taquet, N. / Tomas, L. / Thoreau, E. / Varvier, E. / Vial, E. / Hennequin, L.F.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Impact of Minor Structural Modifications on Properties of a Series of mTOR Inhibitors.
Authors: Ouvry, G. / Clary, L. / Tomas, L. / Aurelly, M. / Bonnary, L. / Borde, E. / Bouix-Peter, C. / Chantalat, L. / Defoin-Platel, C. / Deret, S. / Forissier, M. / Harris, C.S. / Isabet, T. / ...Authors: Ouvry, G. / Clary, L. / Tomas, L. / Aurelly, M. / Bonnary, L. / Borde, E. / Bouix-Peter, C. / Chantalat, L. / Defoin-Platel, C. / Deret, S. / Forissier, M. / Harris, C.S. / Isabet, T. / Lamy, L. / Luzy, A.P. / Pascau, J. / Soulet, C. / Taddei, A. / Taquet, N. / Thoreau, E. / Varvier, E. / Vial, E. / Hennequin, L.F.
History
DepositionJun 21, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 2, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2019Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2May 15, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)112,3782
Polymers112,0541
Non-polymers3241
Water48627
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area40750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.330, 135.780, 143.150
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 / 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: 112053.500 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-FDW / 3-(2-azanyl-1,3-benzoxazol-5-yl)-1-propan-2-yl-pyrazolo[3,4-d]pyrimidine-4,6-diamine


Mass: 324.341 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H16N8O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / Source method: isolated from a natural source / Formula: H2O

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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: 2.57 Å3/Da / Density % sol: 52.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: none

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 17, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 26250 / % possible obs: 99.3 % / Redundancy: 4.4 % / Biso Wilson estimate: 113.46 Å2 / Net I/σ(I): 11.07
Reflection shellResolution: 2.9→2.97 Å / Mean I/σ(I) obs: 0.47 / Num. unique obs: 1859 / % possible all: 96.4

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
XDSdata reduction
MxCuBEdata collection
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→43.15 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.906 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.438
RfactorNum. reflection% reflectionSelection details
Rfree0.232 981 4.86 %RANDOM
Rwork0.18 ---
obs0.182 20171 76.5 %-
Displacement parametersBiso mean: 111.99 Å2
Baniso -1Baniso -2Baniso -3
1--12.1825 Å20 Å20 Å2
2--8.4412 Å20 Å2
3---3.7412 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: 1 / Resolution: 2.9→43.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7368 0 24 27 7419
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.017590HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0810278HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2695SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1310HARMONIC5
X-RAY DIFFRACTIONt_it7590HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.7
X-RAY DIFFRACTIONt_other_torsion19.93
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion963SEMIHARMONIC5
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_contact8447SEMIHARMONIC4
LS refinement shellResolution: 2.9→2.97 Å / Total num. of bins used: 49
RfactorNum. reflection% reflection
Rfree0.2646 -5.1 %
Rwork0.225 391 -
all0.2271 412 -
obs--23.99 %
Refinement TLS params.Method: refined / Origin x: 2.6892 Å / Origin y: 141.914 Å / Origin z: 19.7757 Å
111213212223313233
T-0.4285 Å2-0.1461 Å20.0408 Å2--0.1097 Å20.05 Å2---0.2258 Å2
L2.3606 °20.139 °2-0.3473 °2-1.9252 °20.2627 °2--2.1784 °2
S-0.024 Å °0.4124 Å °0.096 Å °-0.439 Å °0.0989 Å °-0.057 Å °-0.1749 Å °-0.1454 Å °-0.0748 Å °
Refinement TLS groupSelection details: { A|* }

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