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- PDB-6ftn: mPI3Kd IN COMPLEX WITH AZ2 -

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Basic information

Entry
Database: PDB / ID: 6ftn
TitlemPI3Kd IN COMPLEX WITH AZ2
ComponentsPhosphor inositol 3 kinase
KeywordsTRANSFERASE / mI3Kd
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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding 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 ...PI3Kdelta, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding 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 / C2 domain superfamily / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-E78 / 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 Å
AuthorsPetersen, J.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-gamma Inhibitors.
Authors: Pemberton, N. / Mogemark, M. / Arlbrandt, S. / Bold, P. / Cox, R.J. / Gardelli, C. / Holden, N.S. / Karabelas, K. / Karlsson, J. / Lever, S. / Li, X. / Lindmark, H. / Norberg, M. / Perry, M. ...Authors: Pemberton, N. / Mogemark, M. / Arlbrandt, S. / Bold, P. / Cox, R.J. / Gardelli, C. / Holden, N.S. / Karabelas, K. / Karlsson, J. / Lever, S. / Li, X. / Lindmark, H. / Norberg, M. / Perry, M.W.D. / Petersen, J. / Rodrigo Blomqvist, S. / Thomas, M. / Tyrchan, C. / Westin Eriksson, A. / Zlatoidsky, P. / Oster, L.
History
DepositionFeb 22, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 20, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 11, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phosphor inositol 3 kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,1362
Polymers107,7671
Non-polymers3691
Water3,405189
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area37440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.227, 65.012, 116.341
Angle α, β, γ (deg.)90.00, 103.38, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Phosphor inositol 3 kinase


Mass: 107766.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse)
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: O35904
#2: Chemical ChemComp-E78 / ~{N}-[5-[2-[(1~{S})-1-cyclopropylethyl]-7-methyl-1-oxidanylidene-3~{H}-isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl]ethanamide


Mass: 369.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23N3O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 189 / 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 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.25
Details: 50% ethylene glycol/PEG 8000, 0.1 M carboxylic acids mix, 0.1 M Buffer system 2 pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.972 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 29, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.972 Å / Relative weight: 1
ReflectionResolution: 1.98→50 Å / Num. obs: 69187 / % possible obs: 96.6 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.032 / Net I/σ(I): 21.6
Reflection shellResolution: 1.98→2.05 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 5555 / % possible all: 79.3

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Processing

Software
NameVersionClassification
REFMAC5.7.0027refinement
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Internal Model

Resolution: 2→49.69 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.917 / SU B: 5.075 / SU ML: 0.142 / Cross valid method: THROUGHOUT / ESU R: 0.221 / ESU R Free: 0.183 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27238 3450 5.1 %RANDOM
Rwork0.24772 ---
obs0.24899 64184 97.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 41.09 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å2-0 Å2-0.04 Å2
2---0.02 Å20 Å2
3----0.05 Å2
Refinement stepCycle: LAST / Resolution: 2→49.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6675 0 26 189 6890
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0196858
X-RAY DIFFRACTIONr_bond_other_d0.0020.026566
X-RAY DIFFRACTIONr_angle_refined_deg0.8971.9689261
X-RAY DIFFRACTIONr_angle_other_deg0.677315108
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.4465820
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.00124.031320
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.707151242
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.9031541
X-RAY DIFFRACTIONr_chiral_restr0.0470.21021
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.027631
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021591
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.36 227 -
Rwork0.346 3949 -
obs--81.51 %

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