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- PDB-6t3b: Crystal structure of PI3Kgamma with a dihydropurinone inhibitor (... -

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Basic information

Entry
Database: PDB / ID: 6t3b
TitleCrystal structure of PI3Kgamma with a dihydropurinone inhibitor (compound 4)
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / kinase fold / PI3 kinase / type I kinase inhibitor
Function / homology
Function and homology information


secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / dendritic cell chemotaxis / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / positive regulation of Rac protein signal transduction / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / ephrin receptor binding / T cell activation / neutrophil chemotaxis / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / Signaling by CSF1 (M-CSF) in myeloid cells / kinase activity / positive regulation of cytosolic calcium ion concentration / angiogenesis / adaptive immune response / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / protein kinase activity / immune response / inflammatory response / G protein-coupled receptor signaling pathway / phosphorylation / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / ATP binding / membrane / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-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 ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-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-M9T / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.01 Å
AuthorsPetersen, J. / Oster, L. / Schimpl, M. / Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. ...Petersen, J. / Oster, L. / Schimpl, M. / Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Howard, M.R. / Williamson, B. / Davies, B.R. / Cadogan, E.B. / Ramos-Montoya, A. / Dean, E.
CitationJournal: J.Med.Chem. / Year: 2020
Title: The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein ...Title: The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor.
Authors: Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Schimpl, M. / Howard, M.R. / Williamson, B. / Vazquez-Chantada, M. / Barratt, D.G. ...Authors: Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Schimpl, M. / Howard, M.R. / Williamson, B. / Vazquez-Chantada, M. / Barratt, D.G. / Davies, B.R. / Cadogan, E.B. / Ramos-Montoya, A. / Dean, E.
History
DepositionOct 10, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation.year / _citation_author.name
Revision 1.2Apr 22, 2020Group: 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 1.3May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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 gamma isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,1112
Polymers110,7271
Non-polymers3831
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area35310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.045, 67.185, 105.873
Angle α, β, γ (deg.)90.000, 96.640, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 110727.102 Da / Num. of mol.: 1 / Fragment: amino acids 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-M9T / 2-[(4-methoxy-2-methyl-phenyl)amino]-7-methyl-9-(4-oxidanylcyclohexyl)purin-8-one


Mass: 383.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25N5O3
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: 2.25 Å3/Da / Density % sol: 45.33 % / Mosaicity: 0.46 °
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8
Details: 20 % PEG3350, 0.175 M ammonium sulfate, 0.001 M TCEP, 0.1 M Hepes pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 24, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 3.01→44.6 Å / Num. obs: 19204 / % possible obs: 97.4 % / Redundancy: 3.2 % / Biso Wilson estimate: 110.75 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.058 / Rrim(I) all: 0.107 / Net I/σ(I): 8.5 / Num. measured all: 62352
Reflection shellResolution: 3.01→3.12 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.984 / Mean I/σ(I) obs: 1 / Num. measured all: 4944 / Num. unique obs: 1602 / CC1/2: 0.496 / Rpim(I) all: 0.629 / Rrim(I) all: 1.172 / Net I/σ(I) obs: 1 / % possible all: 83.9

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.5.15data scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: unpublished

Resolution: 3.01→39.9 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.887 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.467
RfactorNum. reflection% reflectionSelection details
Rfree0.274 984 5.13 %RANDOM
Rwork0.229 ---
obs0.231 19173 97.3 %-
Displacement parametersBiso max: 213.26 Å2 / Biso mean: 112.71 Å2 / Biso min: 30 Å2
Baniso -1Baniso -2Baniso -3
1-6.2551 Å20 Å2-22.7633 Å2
2--4.0695 Å20 Å2
3----10.3246 Å2
Refine analyzeLuzzati coordinate error obs: 0.51 Å
Refinement stepCycle: final / Resolution: 3.01→39.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6527 0 28 0 6555
Biso mean--90.06 --
Num. residues----804
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2361SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1108HARMONIC5
X-RAY DIFFRACTIONt_it6698HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion865SEMIHARMONIC5
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_contact7491SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6698HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg9060HARMONIC20.94
X-RAY DIFFRACTIONt_omega_torsion1.71
X-RAY DIFFRACTIONt_other_torsion21.56
LS refinement shellResolution: 3.01→3.05 Å / Rfactor Rfree error: 0 / Total num. of bins used: 49
RfactorNum. reflection% reflection
Rfree0.2888 19 4.85 %
Rwork0.3025 373 -
all0.3018 392 -
obs--57.99 %
Refinement TLS params.Method: refined / Origin x: 31.2061 Å / Origin y: -0.1821 Å / Origin z: 25.8275 Å
111213212223313233
T-0.1185 Å20.0019 Å20.0961 Å2--0.304 Å20.0048 Å2---0.2841 Å2
L5.7572 °20.5874 °22.2877 °2-0.7372 °2-0.0342 °2--2.7307 °2
S-0.0999 Å °-0.4399 Å °-0.4213 Å °-0.127 Å °0.2169 Å °-0.1204 Å °-0.2502 Å °-0.2605 Å °-0.117 Å °
Refinement TLS groupSelection details: { A|* }

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