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- PDB-7k6n: Crystal structure of PI3Kalpha selective Inhibitor 11-1575 -

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Basic information

Entry
Database: PDB / ID: 7k6n
TitleCrystal structure of PI3Kalpha selective Inhibitor 11-1575
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsSIGNALING PROTEIN / Transferase / KINASE
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-VY4 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.77 Å
AuthorsChen, P. / Brooun, A. / Deng, Y.L. / Grodsky, N. / Kaiser, S.E.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Based Drug Design and Synthesis of PI3K alpha-Selective Inhibitor (PF-06843195).
Authors: Cheng, H. / Orr, S.T.M. / Bailey, S. / Brooun, A. / Chen, P. / Deal, J.G. / Deng, Y.L. / Edwards, M.P. / Gallego, G.M. / Grodsky, N. / Huang, B. / Jalaie, M. / Kaiser, S. / Kania, R.S. / ...Authors: Cheng, H. / Orr, S.T.M. / Bailey, S. / Brooun, A. / Chen, P. / Deal, J.G. / Deng, Y.L. / Edwards, M.P. / Gallego, G.M. / Grodsky, N. / Huang, B. / Jalaie, M. / Kaiser, S. / Kania, R.S. / Kephart, S.E. / Lafontaine, J. / Ornelas, M.A. / Pairish, M. / Planken, S. / Shen, H. / Sutton, S. / Zehnder, L. / Almaden, C.D. / Bagrodia, S. / Falk, M.D. / Gukasyan, H.J. / Ho, C. / Kang, X. / Kosa, R.E. / Liu, L. / Spilker, M.E. / Timofeevski, S. / Visswanathan, R. / Wang, Z. / Meng, F. / Ren, S. / Shao, L. / Xu, F. / Kath, J.C.
History
DepositionSep 21, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 6, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Mar 6, 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_residues
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)110,4662
Polymers109,9831
Non-polymers4831
Water3,099172
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)57.711, 137.918, 144.046
Angle α, β, γ (deg.)90, 90, 90
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: 109983.094 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-VY4 / tert-butyl (3S)-3-[4-(2-aminopyrimidin-5-yl)-2-(morpholin-4-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate


Mass: 482.579 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H34N8O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 2.61 Å3/Da / Density % sol: 52.8 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop
Details: 8% (w/v) PEG 6000, 0.1 M CHES pH 9.75, 0.64 M sodium formate, 5 mM TCEP pH 7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 20, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.77→144.05 Å / Num. obs: 30108 / % possible obs: 99.9 % / Redundancy: 6.5 % / CC1/2: 0.997 / Net I/σ(I): 15.5
Reflection shellResolution: 2.77→2.92 Å / Num. unique obs: 4285 / CC1/2: 0.752

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 2.77→99.62 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.887 / SU R Cruickshank DPI: 0.946 / Cross valid method: THROUGHOUT / SU R Blow DPI: 1.079 / SU Rfree Blow DPI: 0.309 / SU Rfree Cruickshank DPI: 0.31
RfactorNum. reflection% reflectionSelection details
Rfree0.2347 1403 -RANDOM
Rwork0.1999 ---
obs0.2015 30045 99.9 %-
Displacement parametersBiso mean: 55.54 Å2
Baniso -1Baniso -2Baniso -3
1-3.7155 Å20 Å20 Å2
2---5.6592 Å20 Å2
3---1.9437 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.77→99.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6677 0 35 172 6884
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0086910HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.959446HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2265SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1176HARMONIC5
X-RAY DIFFRACTIONt_it6876HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion921SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact5320SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.84
X-RAY DIFFRACTIONt_other_torsion19.12
LS refinement shellResolution: 2.77→2.79 Å
RfactorNum. reflection% reflection
Rfree0.2973 21 -
Rwork0.2406 --
obs0.2425 601 100 %

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