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- PDB-4v0i: Water Network Determines Selectivity for a Series of Pyrimidone I... -

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Basic information

Entry
Database: PDB / ID: 4v0i
TitleWater Network Determines Selectivity for a Series of Pyrimidone Indoline Amide PI3KBeta Inhibitors over PI3K-Delta
ComponentsPHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM
KeywordsTRANSFERASE / PI3K / KINASE SELECTIVITY
Function / homology
Function and homology information


Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / 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 / phosphatidylinositol 3-kinase complex ...Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / 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 / phosphatidylinositol 3-kinase complex / 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-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / B cell activation / phosphatidylinositol-mediated signaling / B cell homeostasis / homeostasis of number of cells / defense response to fungus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of angiogenesis / chemotaxis / cell migration / kinase activity / adaptive immune response / cell surface receptor signaling pathway / cell differentiation / inflammatory response / phosphorylation / negative regulation of gene expression / innate immune response / positive regulation of gene expression / ATP binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PI3Kdelta, 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 ...PI3Kdelta, 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 delta isoform
Similarity search - Component
Biological speciesMUS MUSCULUS (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.54 Å
AuthorsRobinson, D. / Bertrand, T. / Carry, J.C. / Halley, F. / Karlsson, A. / Mathieu, M. / Minoux, H. / Perrin, M.A. / Robert, B. / Schio, L. / Sherman, W.
CitationJournal: J.Chem.Inf.Model. / Year: 2016
Title: Differential Water Thermodynamics Determine Pi3K-Beta/Delta Selectivity for Solvent-Exposed Ligand Modifications.
Authors: Robinson, D. / Bertrand, T. / Carry, J. / Halley, F. / Karlsson, A. / Mathieu, M. / Minoux, H. / Perrin, M. / Robert, B. / Schio, L. / Sherman, W.
History
DepositionSep 16, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 30, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2016Group: 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 / struct_biol / Item: _exptl_crystal_grow.temp
Revision 1.4Jan 10, 2024Group: 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)216,3564
Polymers215,6472
Non-polymers7092
Water2,522140
1
A: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,1782
Polymers107,8241
Non-polymers3541
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)108,1782
Polymers107,8241
Non-polymers3541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)62.000, 216.430, 76.970
Angle α, β, γ (deg.)90.00, 113.29, 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-KINAS SUBUNIT P110-DELTA / P110DELTA


Mass: 107823.664 Da / Num. of mol.: 2
Fragment: CATALYTIC SUBUNIT DELTA ISOFORM, RESIDUES 106-1043
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Plasmid: PACSG2 / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O35904, 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 / Water


Mass: 18.015 Da / Num. of mol.: 140 / 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: 2.73 Å3/Da / Density % sol: 54.9 % / Description: NONE
Crystal growTemperature: 292 K / pH: 6.5
Details: PEG8000 5-10%, ETHYLENE GLYCOL 10-20%, CARBOXYLIC ACIDS 100MM, IN MES-IMIDAZOLE 100MM BUFFER PH 6.5 AT 19C

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9763
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 17, 2011 / Details: TOROIDAL MIRROR
RadiationMonochromator: DOUBLE CRYSTAL, SI(111) OR SI(311) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.54→216.43 Å / Num. obs: 60528 / % possible obs: 99.4 % / Observed criterion σ(I): 2 / Redundancy: 3.3 % / Biso Wilson estimate: 60.4 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 11.8
Reflection shellResolution: 2.54→2.68 Å / Redundancy: 3 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 2.1 / % possible all: 99.5

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Processing

Software
NameVersionClassification
BUSTER2.9.7refinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WXF

2wxf


Resolution: 2.54→44.7 Å / Cor.coef. Fo:Fc: 0.8799 / Cor.coef. Fo:Fc free: 0.8525 / SU R Cruickshank DPI: 0.673 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.586 / SU Rfree Blow DPI: 0.298 / SU Rfree Cruickshank DPI: 0.309
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rwork0.234 ---
obs0.266 60472 98.84 %-
Rfree-3070 5.08 %RANDOM
Displacement parametersBiso mean: 56.83 Å2
Baniso -1Baniso -2Baniso -3
1-1.3836 Å20 Å2-4.5431 Å2
2---4.1531 Å20 Å2
3---2.7695 Å2
Refine analyzeLuzzati coordinate error obs: 0.385 Å
Refinement stepCycle: LAST / Resolution: 2.54→44.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12462 0 52 140 12654
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00812787HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9517251HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4489SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes310HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1824HARMONIC5
X-RAY DIFFRACTIONt_it12787HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion1.8
X-RAY DIFFRACTIONt_other_torsion20.02
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1594SEMIHARMONIC5
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_contact14175SEMIHARMONIC4
LS refinement shellResolution: 2.54→2.61 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2389 193 4.6 %
Rwork0.2166 4003 -
all0.2176 4196 -
obs--98.84 %

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