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- PDB-4bfr: Discovery and Optimization of Pyrimidone Indoline Amide PI3Kbeta ... -

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Basic information

Entry
Database: PDB / ID: 4bfr
TitleDiscovery and Optimization of Pyrimidone Indoline Amide PI3Kbeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers
ComponentsPHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC S SUBUNIT BETA ISOFORM
KeywordsTRANSFERASE / INHIBITOR
Function / homology
Function and homology information


IRS-mediated signalling / Signaling by ALK / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / Tie2 Signaling / PI3K/AKT activation / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / Downstream signal transduction / GPVI-mediated activation cascade / negative regulation of sprouting angiogenesis ...IRS-mediated signalling / Signaling by ALK / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / Tie2 Signaling / PI3K/AKT activation / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / Downstream signal transduction / GPVI-mediated activation cascade / negative regulation of sprouting angiogenesis / Role of phospholipids in phagocytosis / negative regulation of vascular endothelial growth factor signaling pathway / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / RAF/MAP kinase cascade / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Downstream TCR signaling / Regulation of signaling by CBL / regulation of cell-matrix adhesion / positive regulation of neutrophil apoptotic process / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / embryonic cleavage / angiogenesis involved in wound healing / VEGFA-VEGFR2 Pathway / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / endothelial cell proliferation / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / DAP12 signaling / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / negative regulation of MAPK cascade / 1-phosphatidylinositol-3-kinase activity / positive regulation of Rac protein signal transduction / homophilic cell adhesion via plasma membrane adhesion molecules / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / insulin receptor substrate binding / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / response to ischemia / brush border membrane / platelet activation / autophagy / intracellular calcium ion homeostasis / endocytosis / positive regulation of nitric oxide biosynthetic process / cell migration / kinase activity / midbody / non-specific serine/threonine protein kinase / phosphorylation / protein serine kinase activity / positive regulation of gene expression / nucleolus / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
PI3Kbeta, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain ...PI3Kbeta, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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-J82 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform
Similarity search - Component
Biological speciesMUS MUSCULUS (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsCertal, V. / Carry, J.C. / Halley, F. / Virone-Oddos, A. / Thompson, F. / Filoche-Romme, B. / El-Ahmad, Y. / Karlsson, A. / Charrier, V. / Delorme, C. ...Certal, V. / Carry, J.C. / Halley, F. / Virone-Oddos, A. / Thompson, F. / Filoche-Romme, B. / El-Ahmad, Y. / Karlsson, A. / Charrier, V. / Delorme, C. / Rak, A. / Abecassis, P.Y. / Amara, C. / Vincent, L. / Bonnevaux, H. / Nicolas, J.P. / Mathieu, M. / Bertrand, T. / Marquette, J.P. / Michot, N. / Benard, T. / Perrin, M.A. / Perron, S. / Monget, S. / Gruss-Leleu, F. / Doerflinger, G. / Guizani, H. / Brollo, M. / Delbarre, L. / Bertin, L. / Richepin, P. / Loyau, V. / Garcia-Echeverria, C. / Lengauer, C. / Schio, L.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery and Optimization of Pyrimidone Indoline Amide Pi3Kbeta Inhibitors for the Treatment of Phosphatase and Tensin Homologue (Pten)-Deficient Cancers.
Authors: Certal, V. / Carry, J.B. / Halley, F. / Virone-Oddos, A. / Thompson, F. / Filoche-Romme, B. / El-Ahmad, Y. / Karlsson, A. / Charrier, V. / Delorme, C. / Rak, A. / Abecassis, P. / Amara, C. / ...Authors: Certal, V. / Carry, J.B. / Halley, F. / Virone-Oddos, A. / Thompson, F. / Filoche-Romme, B. / El-Ahmad, Y. / Karlsson, A. / Charrier, V. / Delorme, C. / Rak, A. / Abecassis, P. / Amara, C. / Vincent, L. / Bonnevaux, H. / Nicolas, J. / Mathieu, M. / Bertrand, T. / Marquette, J. / Michot, N. / Benard, T. / Perrin, M. / Lemaitre, O. / Guerif, S. / Perron, S. / Monget, S. / Gruss-Leleu, F. / Doerflinger, G. / Guizani, H. / Brollo, M. / Delbarre, L. / Bertin, L. / Richepin, P. / Loyau, V. / Garcia-Echeverria, C. / Lengauer, C. / Schio, L.
History
DepositionMar 22, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 15, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2014Group: Database references
Revision 1.2Apr 24, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc / pdbx_database_status
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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 S SUBUNIT BETA ISOFORM
B: PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC S SUBUNIT BETA ISOFORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)218,7084
Polymers217,9992
Non-polymers7092
Water1,44180
1
A: PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC S SUBUNIT BETA ISOFORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,3542
Polymers109,0001
Non-polymers3541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC S SUBUNIT BETA ISOFORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,3542
Polymers109,0001
Non-polymers3541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)122.306, 129.034, 154.898
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 S SUBUNIT BETA ISOFORM / PI3-KINASE SUBUNIT BETA / PI3K-BETA / PI3KBETA / PTDINS-3-KINASE SUBUNIT BETA / ...PI3-KINASE SUBUNIT BETA / PI3K-BETA / PI3KBETA / PTDINS-3-KINASE SUBUNIT BETA / PHOSPHATIDYLINOSITOL 4 / 5-BISPHOSPHATE 3-KINASE 110 KDA CATALYTIC SUBUNIT BETA / PTDINS-3-KINASE SUBUNIT P110-BETA / P110BETA


Mass: 108999.742 Da / Num. of mol.: 2 / Fragment: P110BETA CATALYTIC SUBUNIT RESIDUES 114-1064
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q8BTI9, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-J82 / 2-[2-(2-METHYL-2,3-DIHYDRO-INDOL-1-YL)-2-OXO-ETHYL]-6-MORPHOLIN-4-YL-3H-PYRIMIDIN-4-ONE


Mass: 354.403 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H22N4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / 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: 2.8 Å3/Da / Density % sol: 56.12 % / Description: NONE
Crystal growTemperature: 293 K / pH: 7
Details: THE PROTEIN CRYSTALLIZED IN PRESENCE OF 1.7M OF NACL IN 100MM HEPES BUFFER PH 7 AT 20 DEGREES CELSIUS

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1
DetectorType: DECTRIS PILATUS / Detector: PIXEL / Date: Mar 12, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→154.9 Å / Num. obs: 60910 / % possible obs: 99.8 % / Observed criterion σ(I): 2 / Redundancy: 5.9 % / Biso Wilson estimate: 80.73 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 17.8
Reflection shellResolution: 2.8→2.87 Å / Redundancy: 6.3 % / Rmerge(I) obs: 1.27 / Mean I/σ(I) obs: 1.3 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2Y3A

2y3a


Resolution: 2.8→56 Å / Cor.coef. Fo:Fc: 0.8932 / Cor.coef. Fo:Fc free: 0.8782 / SU R Cruickshank DPI: 1.126 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.012 / SU Rfree Blow DPI: 0.356 / SU Rfree Cruickshank DPI: 0.366
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.275 3084 5.07 %RANDOM
Rwork0.26 ---
obs-60840 99.74 %-
Displacement parametersBiso mean: 76.87 Å2
Baniso -1Baniso -2Baniso -3
1--12.9221 Å20 Å20 Å2
2--4.8927 Å20 Å2
3---8.0294 Å2
Refine analyzeLuzzati coordinate error obs: 0.55 Å
Refinement stepCycle: LAST / Resolution: 2.8→56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13645 0 52 80 13777
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00813984HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.8718893HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4982SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes368HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1994HARMONIC5
X-RAY DIFFRACTIONt_it13984HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion1.44
X-RAY DIFFRACTIONt_other_torsion19.85
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1764SEMIHARMONIC5
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_contact15492SEMIHARMONIC4
LS refinement shellResolution: 2.8→2.87 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2983 249 5.59 %
Rwork0.2497 4209 -
all0.2523 4458 -
obs--99.74 %

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