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- PDB-6eyz: PI3 kinase delta in complex with 4-Fluorophenyl 5-(4-(5-((4-isopr... -

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Basic information

Entry
Database: PDB / ID: 6eyz
TitlePI3 kinase delta in complex with 4-Fluorophenyl 5-(4-(5-((4-isopropylpiperazin-1-yl)methyl)oxazol-2-yl)-1H-indazol-6-yl)-2-methoxynicotinate
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / Covalent inhibitor / kinase / drug discovery / complex
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 homeostasis / B cell activation / phosphatidylinositol-mediated signaling / homeostasis of number of cells / defense response to fungus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of angiogenesis / chemotaxis / kinase activity / adaptive immune response / cell differentiation / cell surface receptor signaling pathway / inflammatory response / 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. / C2 phosphatidylinositol 3-kinase-type domain ...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. / 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 / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / C2 domain superfamily / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-C5W / 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 / FOURIER SYNTHESIS / Resolution: 2.2 Å
AuthorsConvery, M.A. / Campos, S. / Dalton, S.E.
CitationJournal: J. Am. Chem. Soc. / Year: 2018
Title: Selectively Targeting the Kinome-Conserved Lysine of PI3K delta as a General Approach to Covalent Kinase Inhibition.
Authors: Dalton, S.E. / Dittus, L. / Thomas, D.A. / Convery, M.A. / Nunes, J. / Bush, J.T. / Evans, J.P. / Werner, T. / Bantscheff, M. / Murphy, J.A. / Campos, S.
History
DepositionNov 13, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 20, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Database references / Category: citation / Item: _citation.title / _citation.year
Revision 1.2Jan 31, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,3282
Polymers120,8511
Non-polymers4771
Water5,531307
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area39850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.830, 64.580, 116.410
Angle α, β, γ (deg.)90.00, 102.29, 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 delta isoform


Mass: 120851.352 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Pik3cd / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q3UDT3, UniProt: O35904*PLUS
#2: Chemical ChemComp-C5W / 2-methoxy-5-[4-[5-[(4-propan-2-ylpiperazin-1-yl)methyl]-1,3-oxazol-2-yl]-2~{H}-indazol-6-yl]pyridine-3-carboxylic acid


Mass: 476.528 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H28N6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 307 / 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: 2.16 Å3/Da / Density % sol: 42.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M buffer system 1 pH 6.5, 0.1 M carboxylic acids, 30% ethylene glycol/PEG 8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Mar 4, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.2→54.06 Å / Num. obs: 51799 / % possible obs: 98.7 % / Redundancy: 3.3 % / Biso Wilson estimate: 53.33 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 12.1
Reflection shellResolution: 2.2→2.26 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.617 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 3857 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.2→54.06 Å / Cor.coef. Fo:Fc: 0.9362 / Cor.coef. Fo:Fc free: 0.9181 / SU R Cruickshank DPI: 0.237 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.236 / SU Rfree Blow DPI: 0.194 / SU Rfree Cruickshank DPI: 0.196
RfactorNum. reflection% reflectionSelection details
Rfree0.2374 2577 4.98 %RANDOM
Rwork0.19 ---
obs0.1924 51775 98.51 %-
Displacement parametersBiso mean: 68.6 Å2
Baniso -1Baniso -2Baniso -3
1--0.7023 Å20 Å2-1.9585 Å2
2--8.8396 Å20 Å2
3----8.1374 Å2
Refine analyzeLuzzati coordinate error obs: 0.289 Å
Refinement stepCycle: 1 / Resolution: 2.2→54.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6940 0 34 307 7281
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.017129HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.079628HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2541SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes177HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1039HARMONIC5
X-RAY DIFFRACTIONt_it7129HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.72
X-RAY DIFFRACTIONt_other_torsion17.74
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion885SEMIHARMONIC5
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_contact8187SEMIHARMONIC4
LS refinement shellResolution: 2.2→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2672 177 4.6 %
Rwork0.2136 3671 -
all0.216 3848 -
obs--99.74 %
Refinement TLS params.Method: refined / Origin x: -20.0727 Å / Origin y: -14.6235 Å / Origin z: 28.9513 Å
111213212223313233
T-0.1772 Å20.0956 Å2-0.0454 Å2--0.1503 Å2-0.0267 Å2---0.2212 Å2
L0.7014 °2-0.0147 °20.0379 °2-0.9922 °20.2662 °2--1.6408 °2
S-0.0343 Å °0.0408 Å °0.137 Å °0.0626 Å °-0.0427 Å °0.1137 Å °-0.073 Å °-0.3784 Å °0.0769 Å °
Refinement TLS groupSelection details: { A|* }

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