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- PDB-4ezj: Potent and Selective Inhibitors of PI3K-delta: Obtaining Isoform ... -

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Basic information

Entry
Database: PDB / ID: 4ezj
TitlePotent and Selective Inhibitors of PI3K-delta: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan Shelf
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase p110 / p110-gamma / lipid kinase / cytoplasmic / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of cardiac muscle contraction / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / secretory granule localization / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / T cell chemotaxis / negative regulation of fibroblast apoptotic process ...negative regulation of cardiac muscle contraction / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / secretory granule localization / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / regulation of calcium ion transmembrane transport / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Co-stimulation by ICOS / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / dendritic cell chemotaxis / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / mast cell degranulation / hepatocyte apoptotic process / phosphatidylinositol-mediated signaling / regulation of cell adhesion mediated by integrin / phosphatidylinositol phosphate biosynthetic process / positive regulation of MAP kinase activity / Synthesis of PIPs at the plasma membrane / positive regulation of Rac protein signal transduction / CD28 dependent PI3K/Akt signaling / regulation of angiogenesis / T cell proliferation / GPVI-mediated activation cascade / ephrin receptor binding / neutrophil chemotaxis / positive regulation of endothelial cell migration / T cell activation / cellular response to cAMP / positive regulation of cytokine production / phosphatidylinositol 3-kinase/protein kinase B signal transduction / platelet aggregation / endocytosis / Constitutive Signaling by Aberrant PI3K in Cancer / G beta:gamma signalling through PI3Kgamma / cell migration / PIP3 activates AKT signaling / positive regulation of cytosolic calcium ion concentration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / angiogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / adaptive immune response / non-specific serine/threonine protein kinase / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein kinase activity / immune response / G protein-coupled receptor signaling pathway / inflammatory response / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / identical protein binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding 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 / 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 ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding 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 / 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-0SC / 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: 2.67 Å
AuthorsMurray, J.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Potent and selective inhibitors of PI3K-delta: obtaining isoform selectivity from the affinity pocket and tryptophan shelf
Authors: Sutherlin, D.P. / Baker, S. / Bisconte, A. / Blaney, P.M. / Brown, A. / Chan, B.K. / Chantry, D. / Castanedo, G. / DePledge, P. / Goldsmith, P. / Goldstein, D.M. / Hancox, T. / Kaur, J. / ...Authors: Sutherlin, D.P. / Baker, S. / Bisconte, A. / Blaney, P.M. / Brown, A. / Chan, B.K. / Chantry, D. / Castanedo, G. / DePledge, P. / Goldsmith, P. / Goldstein, D.M. / Hancox, T. / Kaur, J. / Knowles, D. / Kondru, R. / Lesnick, J. / Lucas, M.C. / Lewis, C. / Murray, J. / Nadin, A.J. / Nonomiya, J. / Pang, J. / Pegg, N. / Price, S. / Reif, K. / Safina, B.S. / Salphati, L. / Staben, S. / Seward, E.M. / Shuttleworth, S. / Sohal, S. / Sweeney, Z.K. / Ultsch, M. / Waszkowycz, B. / Wei, B.
History
DepositionMay 2, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 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)111,2042
Polymers110,6991
Non-polymers5051
Water1,63991
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)141.200, 67.120, 104.770
Angle α, β, γ (deg.)90.00, 97.03, 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 / PI3Kgamma / PtdIns-3-kinase subunit gamma / ...PI3-kinase subunit gamma / PI3K-gamma / PI3Kgamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 110699.023 Da / Num. of mol.: 1 / Fragment: UNP residues 144-1102 / Mutation: K802T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-0SC / 2-(1-{[2-(5-fluoro-1H-indol-4-yl)-4-(morpholin-4-yl)pyrido[3,2-d]pyrimidin-6-yl]methyl}piperidin-4-yl)propan-2-ol


Mass: 504.599 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H33FN6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 91 / 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: 2.23 Å3/Da / Density % sol: 44.73 %
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

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Mar 30, 2011
RadiationProtocol: SINGLE / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.67→55.068 Å / Num. all: 27486 / Num. obs: 27486 / % possible obs: 99 % / Redundancy: 3.6 % / Biso Wilson estimate: 74 Å2 / Rsym value: 0.048 / Net I/σ(I): 14.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRsym valueDiffraction-ID% possible all
2.67-2.823.70.441.80.44199.9
2.82-2.993.70.2622.90.262199.9
2.99-3.23.70.1734.40.1731100
3.2-3.453.70.0967.80.096199.7
3.45-3.783.70.05812.80.058199.8
3.78-4.233.60.04316.70.043198.9
4.23-4.883.50.03320.40.033198.1
4.88-5.983.40.0321.50.03197.2
5.98-8.463.60.02623.50.026196.3
8.46-55.0683.50.02128.10.021193.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASERphasing
BUSTER-TNTrefinement
PDB_EXTRACT3.11data extraction
XSCALEdata scaling
BUSTER2.11.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1E8X

1e8x


Resolution: 2.67→32.04 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.904 / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.268 1406 5.12 %RANDOM
Rwork0.207 ---
obs0.21 27473 98.5 %-
Displacement parametersBiso mean: 69.65 Å2
Baniso -1Baniso -2Baniso -3
1--2.8662 Å20 Å20.2328 Å2
2--0.7902 Å20 Å2
3---2.076 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.67→32.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6703 0 37 91 6831
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016939HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.179399HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2450SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes180HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1007HARMONIC5
X-RAY DIFFRACTIONt_it6939HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.53
X-RAY DIFFRACTIONt_other_torsion21.55
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion903SEMIHARMONIC5
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_contact7976SEMIHARMONIC4
LS refinement shellResolution: 2.67→2.77 Å / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.288 136 4.93 %
Rwork0.2258 2620 -
all0.2288 2756 -
obs--98.47 %

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