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- PDB-5i6u: The crystal structure of PI3Kdelta with compound 32 -

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Basic information

Entry
Database: PDB / ID: 5i6u
TitleThe crystal structure of PI3Kdelta with compound 32
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / p110 / kinase inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Co-stimulation by ICOS / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / CD28 dependent PI3K/Akt signaling / 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 ...Co-stimulation by ICOS / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / CD28 dependent PI3K/Akt signaling / 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 / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / B cell activation / 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 / adaptive immune response / cell differentiation / cell surface receptor signaling pathway / inflammatory response / innate immune response / positive regulation of gene expression / ATP binding / cytosol
Similarity search - Function
PI3Kdelta, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. ...PI3Kdelta, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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-68R / 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: 2.842 Å
AuthorsSomoza, J.R. / Villasenor, A.G.
Citation
Journal: To Be Published
Title: The crystal structure of PI3Kdelta with compound 32
Authors: Somoza, J.R. / Villasenor, A.G.
#1: Journal: Acta Crystallogr. D Biol. Crystallogr. / Year: 2012
Title: Towards automated crystallographic structure refinement with phenix.refine.
Authors: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D.
#2: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2010
Title: PHENIX: a comprehensive Python-based system for macromolecular structure solution.
Authors: Paul D Adams / Pavel V Afonine / Gábor Bunkóczi / Vincent B Chen / Ian W Davis / Nathaniel Echols / Jeffrey J Headd / Li-Wei Hung / Gary J Kapral / Ralf W Grosse-Kunstleve / Airlie J McCoy ...Authors: Paul D Adams / Pavel V Afonine / Gábor Bunkóczi / Vincent B Chen / Ian W Davis / Nathaniel Echols / Jeffrey J Headd / Li-Wei Hung / Gary J Kapral / Ralf W Grosse-Kunstleve / Airlie J McCoy / Nigel W Moriarty / Robert Oeffner / Randy J Read / David C Richardson / Jane S Richardson / Thomas C Terwilliger / Peter H Zwart /
Abstract: Macromolecular X-ray crystallography is routinely applied to understand biological processes at a molecular level. However, significant time and effort are still required to solve and complete many ...Macromolecular X-ray crystallography is routinely applied to understand biological processes at a molecular level. However, significant time and effort are still required to solve and complete many of these structures because of the need for manual interpretation of complex numerical data using many software packages and the repeated use of interactive three-dimensional graphics. PHENIX has been developed to provide a comprehensive system for macromolecular crystallographic structure solution with an emphasis on the automation of all procedures. This has relied on the development of algorithms that minimize or eliminate subjective input, the development of algorithms that automate procedures that are traditionally performed by hand and, finally, the development of a framework that allows a tight integration between the algorithms.
History
DepositionFeb 16, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 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

Downloads & links

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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)108,2502
Polymers107,7671
Non-polymers4831
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)142.836, 64.926, 117.058
Angle α, β, γ (deg.)90.000, 103.172, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / PtdIns-3-kinase subunit delta / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit delta / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit delta / p110delta


Mass: 107766.609 Da / Num. of mol.: 1 / Fragment: UNP residues 106-1043
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: O35904, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-68R / 2-[(1S)-1-({6-amino-5-[(1H-pyrazol-4-yl)ethynyl]pyrimidin-4-yl}amino)ethyl]-5-chloro-3-phenylquinazolin-4(3H)-one


Mass: 482.924 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19ClN8O

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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: 2.45 Å3/Da / Density % sol: 49.84 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: Crystallization protocol can be found in Somoza et al. (2015). JBC 290, pp. 8439-8446.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.977 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 7, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionResolution: 2.84→30 Å / Num. obs: 24148 / % possible obs: 97.4 % / Redundancy: 3.4 % / Biso Wilson estimate: 57.003 Å2 / Rmerge(I) obs: 0.132 / Net I/av σ(I): 11.891 / Net I/σ(I): 7.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.85-2.92.20.67183.8
2.9-2.952.30.681187.1
2.95-3.012.70.645194.3
3.01-3.072.90.589195.1
3.07-3.143.30.521197.9
3.14-3.213.50.45198.8
3.21-3.293.60.388199.3
3.29-3.383.70.333198.9
3.38-3.483.70.282199
3.48-3.593.70.226199.4
3.59-3.723.70.187199.2
3.72-3.873.70.161199.6
3.87-4.043.70.137199.3
4.04-4.253.70.117199.2
4.25-4.523.70.101199.1
4.52-4.873.60.091199.3
4.87-5.363.60.091199.5
5.36-6.123.60.099199.2
6.12-7.693.50.078199.6
7.69-303.50.05199.4

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XE0

4xe0


Resolution: 2.842→29.662 Å / SU ML: 0.489828277376 / Cross valid method: FREE R-VALUE / σ(F): 1.341 / Phase error: 33.764564163
RfactorNum. reflection% reflectionSelection details
Rfree0.3066 1999 8.28120468951 %1
Rwork0.212 ---
obs0.22 24139 96.9243123871 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 53.7675292773 Å2
Refinement stepCycle: LAST / Resolution: 2.842→29.662 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3185 0 3437 0 6622
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01413397559746766
X-RAY DIFFRACTIONf_angle_d1.726837529099126
X-RAY DIFFRACTIONf_chiral_restr0.06296889400041004
X-RAY DIFFRACTIONf_plane_restr0.007635408193691152
X-RAY DIFFRACTIONf_dihedral_angle_d17.37299316412512
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.842-2.91270.4154768131131180.2889043236711298X-RAY DIFFRACTION79.4167134044
2.9127-2.99130.3947549842451310.2972556910111461X-RAY DIFFRACTION91.546866015
2.9913-3.07930.379957320141410.2577814477981552X-RAY DIFFRACTION94.899103139
3.0793-3.17860.3765475045131430.2374114844371586X-RAY DIFFRACTION98.6309184256
3.1786-3.2920.3451335196341440.2340106451991588X-RAY DIFFRACTION98.9149057681
3.292-3.42360.3230383674151480.2328601717881639X-RAY DIFFRACTION99.0027700831
3.4236-3.57920.3590138458151440.2179292081261599X-RAY DIFFRACTION99.1467576792
3.5792-3.76760.3327605347011440.2159038613221593X-RAY DIFFRACTION99.3138936535
3.7676-4.00310.3285721122091450.1951460935881619X-RAY DIFFRACTION99.2684299381
4.0031-4.31130.2804786612621480.1883331576431629X-RAY DIFFRACTION99.2737430168
4.3113-4.74360.2778644610751440.1815418819051605X-RAY DIFFRACTION99.2058990357
4.7436-5.42640.27926478921470.1839660953571632X-RAY DIFFRACTION99.3299832496
5.4264-6.82290.2660488918661480.2380187665971637X-RAY DIFFRACTION99.4428969359
6.8229-29.6640.2620386305781540.1998367464951702X-RAY DIFFRACTION99.4108194965

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