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- PDB-4ajw: Discovery and Optimization of New Benzimidazole- and Benzoxazole-... -

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Entry
Database: PDB / ID: 4ajw
TitleDiscovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3KBeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers
ComponentsPHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM
KeywordsTRANSFERASE / P110D
Function / homology
Function and homology information


Co-stimulation by ICOS / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / CD28 dependent PI3K/Akt signaling / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling ...Co-stimulation by ICOS / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / CD28 dependent PI3K/Akt signaling / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / positive regulation of epithelial tube formation / positive regulation of neutrophil apoptotic process / phosphatidylinositol 3-kinase complex / 1-phosphatidylinositol-4-phosphate 3-kinase activity / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / vascular endothelial growth factor signaling pathway / phosphatidylinositol-mediated signaling / B cell homeostasis / B cell activation / homeostasis of number of cells / defense response to fungus / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / chemotaxis / positive regulation of angiogenesis / cell migration / adaptive immune response / cell differentiation / cell surface receptor signaling pathway / positive regulation of cell migration / inflammatory response / negative regulation of gene expression / innate immune response / positive regulation of gene expression / ATP binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
PI3Kdelta, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. ...PI3Kdelta, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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. / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / C2 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-VWN / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Similarity search - Component
Biological speciesMUS MUSCULUS (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsCertal, V. / Halley, F. / Virone-Oddos, A. / Delorme, C. / Karlsson, A. / Rak, A. / Thompson, F. / Filoche-Romme, B. / El-Ahmad, Y. / Carry, J.C. ...Certal, V. / Halley, F. / Virone-Oddos, A. / Delorme, C. / Karlsson, A. / Rak, A. / Thompson, F. / Filoche-Romme, B. / El-Ahmad, Y. / Carry, J.C. / Abecassis, P.Y. / Lejeune, P. / Bonnevaux, H. / Nicolas, J.P. / Bertrand, T. / Marquette, J.P. / Michot, N. / Benard, T. / Below, P. / Vade, I. / Chatreaux, F. / Lebourg, G. / Pilorge, F. / Angouillant-Boniface, O. / Louboutin, A. / Lengauer, C. / Schio, L.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective Pi3Kbeta Inhibitors for the Treatment of Phosphatase and Tensin Homologue (Pten)-Deficient Cancers.
Authors: Certal, V. / Halley, F. / Virone-Oddos, A. / Delorme, C. / Karlsson, A. / Rak, A. / Thompson, F. / Filoche-Romm, B. / El-Ahmad, Y. / Carry, J.C. / Abecassis, P.Y. / Lejeune, P. / Vincent, L. ...Authors: Certal, V. / Halley, F. / Virone-Oddos, A. / Delorme, C. / Karlsson, A. / Rak, A. / Thompson, F. / Filoche-Romm, B. / El-Ahmad, Y. / Carry, J.C. / Abecassis, P.Y. / Lejeune, P. / Vincent, L. / Bonnevaux, H. / Nicolas, J.P. / Bertrand, T. / Marquette, J.P. / Michot, N. / Benard, T. / Below, P. / Vade, I. / Chatreaux, F. / Lebourg, G. / Pilorge, F. / Angouillant-Boniface, O. / Louboutin, A. / Lengauer, C. / Schio, L.
History
DepositionFeb 20, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 6, 2012Group: Other
Revision 1.2Mar 29, 2017Group: Structure summary
Revision 1.3Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
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 SUBUNIT DELTA ISOFORM
B: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)215,0714
Polymers214,4202
Non-polymers6512
Water61334
1
A: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,5352
Polymers107,2101
Non-polymers3251
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,5352
Polymers107,2101
Non-polymers3251
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)63.400, 220.470, 78.260
Angle α, β, γ (deg.)90.00, 113.87, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM / PI3-KINASE SUBUNIT DELTA / PI3K-DELTA / PI3KDELTA / PTDINS-3-KINASE SUBUNIT DELTA / ...PI3-KINASE SUBUNIT DELTA / PI3K-DELTA / PI3KDELTA / PTDINS-3-KINASE SUBUNIT DELTA / PHOSPHATIDYLINOSITOL-4 / 5-BISPHOSPHATE 3-KINASE 110 KDA CATALYTIC SUBUNIT DELTA / PTDINS-3-KINASE SUBUNIT P110-DELTA / P110DELTA


Mass: 107210.023 Da / Num. of mol.: 2 / Fragment: RESIDUES 110-1044
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: O35904, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-VWN / 2-[(1-methyl-1H-benzimidazol-2-yl)methyl]-6-morpholin-4-ylpyrimidin-4(3H)-one


Mass: 325.365 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H19N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 34 / 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 % / Description: NONE
Crystal growpH: 6.5
Details: 14-16% PEG 8000 28-32% ETHYLENE GLYCOL 100 MM CARBOXYLIC ACIDS 100 MM MES/IMIDAZOLE, PH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.9784
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 26, 2011 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9784 Å / Relative weight: 1
ReflectionResolution: 2.8→71.6 Å / Num. obs: 47547 / % possible obs: 98.4 % / Observed criterion σ(I): 2 / Redundancy: 3.3 % / Biso Wilson estimate: 84.98 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 10.1
Reflection shellResolution: 2.8→2.87 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 2.4 / % possible all: 99.5

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Processing

Software
NameVersionClassification
BUSTER-TNT2.9.7refinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WXF

2wxf


Resolution: 2.8→71.57 Å / Cor.coef. Fo:Fc: 0.8736 / Cor.coef. Fo:Fc free: 0.8569 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.383
RfactorNum. reflection% reflectionSelection details
Rfree0.277 2433 5.1 %RANDOM
Rwork0.252 ---
obs-47377 98.36 %-
Displacement parametersBiso mean: 74.83 Å2
Baniso -1Baniso -2Baniso -3
1--11.0778 Å20 Å21.6752 Å2
2--3.0863 Å20 Å2
3---7.9916 Å2
Refinement stepCycle: LAST / Resolution: 2.8→71.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12514 0 48 34 12596
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00712835HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.8717313HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4531SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes312HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1861HARMONIC5
X-RAY DIFFRACTIONt_it12835HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion1.44
X-RAY DIFFRACTIONt_other_torsion20.33
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1599SEMIHARMONIC5
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_contact13903SEMIHARMONIC4
LS refinement shellResolution: 2.8→2.87 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2575 192 5.45 %
Rwork0.2506 3329 -
all0.251 3521 -
obs--98.36 %

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