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- PDB-5t7f: PI3Kdelta in complex with the inhibitor GS-643624 -

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Basic information

Entry
Database: PDB / ID: 5t7f
TitlePI3Kdelta in complex with the inhibitor GS-643624
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTransferase/Transferase Inhibitor / PI3Kdelta phosphatidylinositol-3-kinase PI(3)K / Transferase-Transferase Inhibitor 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 / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling ...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 / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / positive regulation of epithelial tube formation / positive regulation of neutrophil apoptotic process / 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-kinase complex, class IA / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / B cell activation / B cell homeostasis / homeostasis of number of cells / defense response to fungus / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / 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 / positive regulation of cell migration / 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 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain ...PI3Kdelta, catalytic domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / C2 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 / 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-76C / 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: 2.6 Å
AuthorsSomoza, J.R. / Villasenor, A.
CitationJournal: To Be Published
Title: The Discovery of GS-9901: A Potent, Selective and Metabolically Stable Inhibitor of PI3Kd
Authors: Patel, L. / Chandrasekhar, J. / Evarts, J. / Forseth, K. / Haran, A. / Ip, C. / Kashishian, A. / Kim, M. / Koditek, D. / Koppenol, S. / Lad, L. / Lepist, E.-I. / McGrath, M.E. / Perreault, S. ...Authors: Patel, L. / Chandrasekhar, J. / Evarts, J. / Forseth, K. / Haran, A. / Ip, C. / Kashishian, A. / Kim, M. / Koditek, D. / Koppenol, S. / Lad, L. / Lepist, E.-I. / McGrath, M.E. / Perreault, S. / Puri, K. / Villasenor, A. / Somoza, J.R. / Steiner, B. / Therrien, J. / Trilberg, J. / Phillips, G.
History
DepositionSep 4, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 28, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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
B: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)216,4654
Polymers215,5332
Non-polymers9322
Water1,71195
1
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,2322
Polymers107,7671
Non-polymers4661
Water181
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)108,2322
Polymers107,7671
Non-polymers4661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.226, 142.794, 221.067
Angle α, β, γ (deg.)90.0, 90.055, 90.0
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.: 2 / 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-76C / 2,4-bis(azanyl)-6-[[(1~{S})-1-[5-chloranyl-3-(5-fluoranyl-4-methyl-pyridin-3-yl)-4-oxidanylidene-quinazolin-2-yl]ethyl]amino]pyrimidine-5-carbonitrile


Mass: 465.871 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H17ClFN9O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 95 / 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: 2.7 Å3/Da / Density % sol: 54.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: Crystals used for seeding were obtained by vapor diffusion at 20 degrees C with 25 nl of 11 mg/ml (delta)ABD-p110(delta) and 0.9 mM of a p110(delta) inhibitor in protein storage buffer (20 ...Details: Crystals used for seeding were obtained by vapor diffusion at 20 degrees C with 25 nl of 11 mg/ml (delta)ABD-p110(delta) and 0.9 mM of a p110(delta) inhibitor in protein storage buffer (20 mM Tris, pH 7.2, 50 mM (NH4)2SO4, 1% v/v ethylene glycol, 1% (w/v) betaine, 0.3 microM CHAPS, and 5 mM TCEP) added to 25 nl of reservoir solution (25% (w/v) PEG 3350, 0.1 M bis-tris (pH 6.5). Crystals were pulverized, pooled together in the reservoir solution, vortexed with a Seed-Bead (Hampton Research) for 45 s, flash-frozen in liquid nitrogen, and stored at minus 80 degrees C. For seeding crystallization trials, the frozen seed was thawed and diluted 500-fold in 25% (v/v) PEG 300, 0.1 M Tris (pH 8.5). Preparation of diffraction quality (delta)ABD-p110(delta):idelalisib crystals started with a mixture of 0.48 microliters of 2.5% (w/v) n-dodecyl-(beta)-D-maltoside, 0.30 microliters of 20 mM ligand, and 12 microliters of 12 mg/ml (delta)ABD-p110(delta) in storage buffer (described above). The mixture was allowed to sit for 1 h at room temperature instead of 4 degrees C to prevent the formation of white precipitate. Seeded vapor diffusion droplets were assembled by adding 90 nl of the 500-fold diluted seed (described above) to 100 nl of the n-dodecyl-(beta)-D-maltoside-ligand-(delta)ABD-p110(delta) mixture. The droplets were equilibrated against reservoir wells containing 50 microliters of 1% to 30% (v/v) PEG 300, 0.1 M Tris (pH 8.5) at 20 degrees C. Crystals appeared in 2 to 5 days across the 1% to 30% PEG range. Crystals were cryoprotected in 20% (w/v) glycerol, 25% (w/v) PEG 300, 0.1 M Tris (pH 8.5), 50 mM ammonium sulfate, 0.2% (w/v) n-dodecyl-(beta)-D-maltoside, 0.2 mM ligand and were flash-frozen in liquid nitrogen for data collection.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 27, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 56178 / % possible obs: 91.8 % / Redundancy: 3.4 % / Biso Wilson estimate: 52.15 Å2 / Net I/σ(I): 15.3
Reflection shellResolution: 2.6→2.64 Å / Redundancy: 3 % / Mean I/σ(I) obs: 1.2 / CC1/2: 0.58 / % possible all: 81.6

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
SCALEPACKdata scaling
EPMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→45.9 Å / SU ML: 0.413 / Cross valid method: FREE R-VALUE / σ(F): 1.335 / Phase error: 33.9
RfactorNum. reflection% reflection
Rfree0.294 1983 3.53 %
Rwork0.23 54166 -
obs0.23 56149 91.36 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 63.31 Å2
Refinement stepCycle: LAST / Resolution: 2.6→45.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13178 0 66 95 13339
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0039531512051513546
X-RAY DIFFRACTIONf_angle_d0.77596531074218283
X-RAY DIFFRACTIONf_chiral_restr0.0310673728622017
X-RAY DIFFRACTIONf_plane_restr0.003036561790632308
X-RAY DIFFRACTIONf_dihedral_angle_d13.9839724985019
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.66160.40571190.29773273X-RAY DIFFRACTION77.38
2.6616-2.73350.34251330.28783612X-RAY DIFFRACTION86.05
2.7335-2.81390.39851330.28713679X-RAY DIFFRACTION87.09
2.8139-2.90480.35541370.28553673X-RAY DIFFRACTION86.63
2.9048-3.00860.37391370.2833694X-RAY DIFFRACTION87.64
3.0086-3.1290.3631300.28713701X-RAY DIFFRACTION87.98
3.129-3.27140.41031350.26573734X-RAY DIFFRACTION88.65
3.2714-3.44380.31241350.25533867X-RAY DIFFRACTION91.12
3.4438-3.65940.29681450.23933926X-RAY DIFFRACTION92.79
3.6594-3.94190.261510.22424077X-RAY DIFFRACTION96.37
3.9419-4.33830.25671540.20334204X-RAY DIFFRACTION98.57
4.3383-4.96540.27731570.19954193X-RAY DIFFRACTION99.26
4.9654-6.25330.28561530.22784242X-RAY DIFFRACTION99.88
6.2533-45.87950.241640.19974291X-RAY DIFFRACTION99.26

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