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- PDB-3r7r: Structure-based design of thienobenzoxepin inhibitors of PI3-Kinase -

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Basic information

Entry
Database: PDB / ID: 3r7r
TitleStructure-based design of thienobenzoxepin inhibitors of PI3-Kinase
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase p110 / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / phosphatidylinositol 3-kinase complex, class IA / 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 / T cell activation / ephrin receptor binding / 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-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / C2 domain superfamily / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Ubiquitin-like (UB roll) / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Roll / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-FAZ / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsMurray, J.M. / Wiesmann, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Structure-based design of thienobenzoxepin inhibitors of PI3-kinase.
Authors: Staben, S.T. / Siu, M. / Goldsmith, R. / Olivero, A.G. / Do, S. / Burdick, D.J. / Heffron, T.P. / Dotson, J. / Sutherlin, D.P. / Zhu, B.Y. / Tsui, V. / Le, H. / Lee, L. / Lesnick, J. / ...Authors: Staben, S.T. / Siu, M. / Goldsmith, R. / Olivero, A.G. / Do, S. / Burdick, D.J. / Heffron, T.P. / Dotson, J. / Sutherlin, D.P. / Zhu, B.Y. / Tsui, V. / Le, H. / Lee, L. / Lesnick, J. / Lewis, C. / Murray, J.M. / Nonomiya, J. / Pang, J. / Prior, W.W. / Salphati, L. / Rouge, L. / Sampath, D. / Sideris, S. / Wiesmann, C. / Wu, P.
History
DepositionMar 22, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 3, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 5, 2012Group: Database references
Revision 1.2Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.location / _software.name / _software.type / _software.version
Revision 1.3Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)111,1542
Polymers110,7271
Non-polymers4271
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)143.792, 67.868, 106.933
Angle α, β, γ (deg.)90.00, 95.40, 90.00
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 / PI3-kinase subunit gamma / PI3K-gamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol-4 / 5- ...PI3-kinase subunit gamma / PI3K-gamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol-4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p120-PI3K


Mass: 110727.102 Da / Num. of mol.: 1 / Fragment: unp residues 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Cell (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-FAZ / 8-(acetylamino)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrothieno[3,2-d][1]benzoxepine-2-carboxamide


Mass: 426.916 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H19ClN2O3S

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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: 2.27 Å3/Da / Density % sol: 45.9 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: PEG 3350, 0.2M NH4SO4, 0.1M Tris-HCl 8.5, vapor diffusion, hanging drop, temperature 289K

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Data collection

Diffraction
IDCrystal-ID
11
21
Diffraction source
SourceSiteBeamlineIDWavelength (Å)
SYNCHROTRONALS 5.0.211
21
Detector
TypeIDDetectorDate
MAR1CCDMay 17, 2007
ADSC2CCDNov 6, 2007
Radiation
IDProtocolScattering typeWavelength-ID
1SINGLEx-ray1
2SINGLEx-ray1
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 34114 / % possible obs: 98.6 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.042 / Net I/σ(I): 15.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.5-2.592.40.5491,294.6
2.59-2.692.70.4681,298.6
2.69-2.822.90.3461,299.2
2.82-2.962.90.2281,299.2
2.96-3.152.90.1471,299.3
3.15-3.392.90.0871,299.3
3.39-3.732.90.0541,299.4
3.73-4.272.90.0381,299.6
4.27-5.382.80.0281,299.6
5.38-502.70.0231,297.1

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Processing

Software
NameVersionClassificationNB
PHENIXdev_806refinement
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3e8x

3e8x


Resolution: 2.9→19.927 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.923 / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.62 / SU R Cruickshank DPI: 0.6749 / σ(F): 1.34 / Phase error: 27.89 / Stereochemistry target values: ML / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rfree0.2531 1179 5.15 %
Rwork0.207 --
obs0.2094 22879 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60.774 Å2 / ksol: 0.272 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-3.6067 Å20 Å27.4414 Å2
2--2.6581 Å2-0 Å2
3----6.2648 Å2
Refinement stepCycle: LAST / Resolution: 2.9→19.927 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6775 0 29 0 6804
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0116952
X-RAY DIFFRACTIONf_angle_d1.5629408
X-RAY DIFFRACTIONf_dihedral_angle_d16.9552581
X-RAY DIFFRACTIONf_chiral_restr0.1161055
X-RAY DIFFRACTIONf_plane_restr0.011196
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-3.03160.34391590.28472678X-RAY DIFFRACTION100
3.0316-3.19080.31431570.27582702X-RAY DIFFRACTION100
3.1908-3.38980.34131200.26022720X-RAY DIFFRACTION100
3.3898-3.650.3071550.23842690X-RAY DIFFRACTION100
3.65-4.01460.23731440.21332714X-RAY DIFFRACTION100
4.0146-4.58940.19461560.17832693X-RAY DIFFRACTION100
4.5894-5.75890.26971470.18982743X-RAY DIFFRACTION100
5.7589-19.92710.23141410.19332760X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 32.8851 Å / Origin y: 47.0431 Å / Origin z: 26.4657 Å
111213212223313233
T-0.0941 Å20.0309 Å20.0152 Å2--0.3167 Å20.0125 Å2---0.2466 Å2
L4.1281 °2-0.6136 °20.583 °2-1.1076 °2-0.0931 °2--2.045 °2
S-0.1221 Å °-0.353 Å °0.0495 Å °0.2687 Å °0.1715 Å °0.2089 Å °-0.2518 Å °-0.1837 Å °-0.0494 Å °

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