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- PDB-6mum: Murine PI3K delta kinsae domain - cpd 3 -

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Basic information

Entry
Database: PDB / ID: 6mum
TitleMurine PI3K delta kinsae domain - cpd 3
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / PHOSPHOINOSITIDE 3-KINASE / ISOFORM-SPECIFIC INHIBITORS / INFLAMMATORY DISORDERS
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 / cytoplasm / cytosol
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-K47 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / phosphatidylinositol-4,5-bisphosphate 3-kinase
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.06 Å
AuthorsFischmann, T.O.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Structure Overhaul Affords a Potent Purine PI3K delta Inhibitor with Improved Tolerability.
Authors: Methot, J.L. / Zhou, H. / Kattar, S.D. / McGowan, M.A. / Wilson, K. / Garcia, Y. / Deng, Y. / Altman, M. / Fradera, X. / Lesburg, C. / Fischmann, T. / Li, C. / Alves, S. / Shah, S. / ...Authors: Methot, J.L. / Zhou, H. / Kattar, S.D. / McGowan, M.A. / Wilson, K. / Garcia, Y. / Deng, Y. / Altman, M. / Fradera, X. / Lesburg, C. / Fischmann, T. / Li, C. / Alves, S. / Shah, S. / Fernandez, R. / Goldenblatt, P. / Hill, A. / Shaffer, L. / Chen, D. / Tong, V. / McLeod, R.L. / Yu, H. / Bass, A. / Kemper, R. / Gatto, N.T. / LaFranco-Scheuch, L. / Trotter, B.W. / Guzi, T. / Katz, J.D.
History
DepositionOct 23, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2019Provider: repository / Type: Initial release
Revision 1.1May 22, 2019Group: 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_author.name
Revision 1.2Oct 11, 2023Group: 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: 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)216,5264
Polymers215,6472
Non-polymers8792
Water00
1
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,2632
Polymers107,8241
Non-polymers4401
Water0
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)108,2632
Polymers107,8241
Non-polymers4401
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)63.350, 220.680, 78.190
Angle α, β, γ (deg.)90.00, 114.02, 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


Mass: 107823.664 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Pik3cd / Cell line (production host): SF21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q3UDT3, UniProt: O35904*PLUS, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-K47 / [(3S)-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidin-1-yl](oxan-4-yl)methanone


Mass: 439.511 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H29N7O3 / Feature type: SUBJECT OF INVESTIGATION

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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: 2.31 Å3/Da / Density % sol: 46.87 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: 0.1M Na-MES pH 6.8, 30 mM Na2HPO4, 5% v/v MPD, 13% w/v PEG600

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.055→31.04 Å / Num. obs: 34556 / % possible obs: 93.4 % / Redundancy: 3.2 % / Biso Wilson estimate: 105.96 Å2 / Net I/σ(I): 10.4
Reflection shellResolution: 3.055→3.066 Å / Redundancy: 3.3 % / % possible all: 99.1

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Processing

Software
NameVersionClassification
XDSdata reduction
XDSdata reduction
SCALAdata scaling
BUSTER2.11.7refinement
BUSTER-TNTphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2WXF

2wxf


Resolution: 3.06→30.45 Å / Cor.coef. Fo:Fc: 0.908 / Cor.coef. Fo:Fc free: 0.89 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.494
RfactorNum. reflection% reflectionSelection details
Rfree0.266 1734 5.02 %RANDOM
Rwork0.23 ---
obs0.232 34523 93.3 %-
Displacement parametersBiso mean: 97.93 Å2
Baniso -1Baniso -2Baniso -3
1--12.8767 Å20 Å2-11.4429 Å2
2--4.8798 Å20 Å2
3---7.9969 Å2
Refine analyzeLuzzati coordinate error obs: 0.52 Å
Refinement stepCycle: LAST / Resolution: 3.06→30.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13294 0 64 0 13358
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00826987HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9748785HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5959SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes4220HARMONIC5
X-RAY DIFFRACTIONt_it26987HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.63
X-RAY DIFFRACTIONt_other_torsion16.47
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1698SEMIHARMONIC5
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_contact28123SEMIHARMONIC4
LS refinement shellResolution: 3.06→3.08 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.364 -4.92 %
Rwork0.2607 657 -
all0.2657 691 -
obs--97.17 %

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