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- PDB-7z61: Crystal structure of PI3Kgamma with a dihydropurinone inhibitor (... -

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Basic information

Entry
Database: PDB / ID: 7z61
TitleCrystal structure of PI3Kgamma with a dihydropurinone inhibitor (compound 18)
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsSIGNALING PROTEIN / type I kinase inhibitor / structure-baed drug design
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-IGJ / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.738 Å
AuthorsGoldberg, F.W. / Ting, A.K.T. / Schimpl, M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Not funded United Kingdom
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8 H -purin-8-one Inhibitors of DNA-PK.
Authors: Goldberg, F.W. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Finlay, M.R.V. / Williamson, B. / Schimpl, M. / Harmer, A.R. / Adeyemi, O.B. / Nordell, P. / Cronin, A.S. / Vazquez- ...Authors: Goldberg, F.W. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Finlay, M.R.V. / Williamson, B. / Schimpl, M. / Harmer, A.R. / Adeyemi, O.B. / Nordell, P. / Cronin, A.S. / Vazquez-Chantada, M. / Barratt, D. / Ramos-Montoya, A. / Cadogan, E.B. / Davies, B.R.
History
DepositionMar 10, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 13, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 1, 2024Group: 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

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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)111,1212
Polymers110,7271
Non-polymers3931
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area36550 Å2
Unit cell
Length a, b, c (Å)142.894, 67.950, 107.464
Angle α, β, γ (deg.)90.000, 95.920, 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-IGJ / 9-[(3~{R},4~{R})-4-fluoranylpyrrolidin-3-yl]-7-methyl-2-[(7-methylquinolin-6-yl)amino]purin-8-one


Mass: 393.418 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20FN7O / Feature type: SUBJECT OF INVESTIGATION
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: 2.34 Å3/Da / Density % sol: 47.51 % / Mosaicity: 0 °
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: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 27, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.738→62.21 Å / Num. obs: 26986 / % possible obs: 99.2 % / Redundancy: 3.3 % / Biso Wilson estimate: 129.48 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.037 / Rpim(I) all: 0.024 / Rrim(I) all: 0.045 / Net I/σ(I): 11.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.74-2.813.40.796675419800.6030.5020.944199.3
12.25-62.1630.0218082720.9960.0140.02530.381.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
AMoREphasing
BUSTER2.11.8 (24-FEB-2021)refinement
PDB_EXTRACT3.27data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 2.738→62.21 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.935 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.51 / SU Rfree Blow DPI: 0.364
RfactorNum. reflection% reflectionSelection details
Rfree0.2757 1317 4.88 %RANDOM
Rwork0.2174 ---
obs0.2203 26976 98.9 %-
Displacement parametersBiso max: 220.39 Å2 / Biso mean: 141.29 Å2 / Biso min: 80.6 Å2
Baniso -1Baniso -2Baniso -3
1-7.3619 Å20 Å20.5769 Å2
2---10.489 Å20 Å2
3---3.1271 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
Refinement stepCycle: final / Resolution: 2.738→62.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6749 0 29 0 6778
Biso mean--109.33 --
Num. residues----834
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2452SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1153HARMONIC5
X-RAY DIFFRACTIONt_it6927HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion900SEMIHARMONIC5
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_contact5130SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6927HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg9377HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion2.72
X-RAY DIFFRACTIONt_other_torsion20.65
LS refinement shellResolution: 2.74→2.76 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3066 30 5.56 %
Rwork0.3204 510 -
all0.3196 540 -
obs--90.74 %
Refinement TLS params.Method: refined / Origin x: 32.3272 Å / Origin y: -0.014 Å / Origin z: 26.2773 Å
111213212223313233
T-0.1958 Å20.0205 Å20.0679 Å2--0.5091 Å2-0.0399 Å2---0.2561 Å2
L7.2362 °21.2366 °21.2433 °2-1.5413 °20.065 °2--3.8571 °2
S0.0473 Å °-0.1307 Å °-0.0404 Å °-0.0789 Å °0.0174 Å °-0.3617 Å °-0.5213 Å °0.1334 Å °-0.0647 Å °
Refinement TLS groupSelection details: { A|* }

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