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- PDB-3l13: Crystal Structures of Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR... -

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Basic information

Entry
Database: PDB / ID: 3l13
TitleCrystal Structures of Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / kinase / ATP-binding / Nucleotide-binding / PI3K-gamma p110 gamma
Function / homology
Function and homology information


secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / dendritic cell chemotaxis / 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 / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / positive regulation of Rac protein signal transduction / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / T cell activation / ephrin receptor binding / neutrophil chemotaxis / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / Signaling by CSF1 (M-CSF) in myeloid cells / kinase activity / positive regulation of cytosolic calcium ion concentration / angiogenesis / adaptive immune response / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / protein kinase activity / immune response / inflammatory response / G protein-coupled receptor signaling pathway / phosphorylation / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / ATP binding / membrane / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding 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 / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding 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 / 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-JZW / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3 Å
AuthorsMurray, J.M. / Wiesmann, C.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Discovery of (Thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer.
Authors: Sutherlin, D.P. / Sampath, D. / Berry, M. / Castanedo, G. / Chang, Z. / Chuckowree, I. / Dotson, J. / Folkes, A. / Friedman, L. / Goldsmith, R. / Heffron, T. / Lee, L. / Lesnick, J. / Lewis, ...Authors: Sutherlin, D.P. / Sampath, D. / Berry, M. / Castanedo, G. / Chang, Z. / Chuckowree, I. / Dotson, J. / Folkes, A. / Friedman, L. / Goldsmith, R. / Heffron, T. / Lee, L. / Lesnick, J. / Lewis, C. / Mathieu, S. / Nonomiya, J. / Olivero, A. / Pang, J. / Prior, W.W. / Salphati, L. / Sideris, S. / Tian, Q. / Tsui, V. / Wan, N.C. / Wang, S. / Wiesmann, C. / Wong, S. / Zhu, B.Y.
History
DepositionDec 10, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 16, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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 gamma isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,4022
Polymers109,8981
Non-polymers5041
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.359, 67.741, 107.151
Angle α, β, γ (deg.)90.000, 95.630, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform / PI3-kinase p110 subunit gamma / PtdIns-3-kinase subunit p110 / PI3Kgamma / PI3K / p120-PI3K


Mass: 109898.203 Da / Num. of mol.: 1 / Fragment: UNP residues 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-JZW / [3-(6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-4-morpholin-4-ylthieno[3,2-d]pyrimidin-2-yl)phenyl]methanol


Mass: 503.637 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29N5O4S2

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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: 2.37 Å3/Da / Density % sol: 48.15 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: PEG 3350, 0.2M NH4SO4, 0.1M Tris-HCl 8.5, vapor diffusion, hanging drop, temperature 289K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 15, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 21245 / % possible obs: 99.9 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.061 / Χ2: 1.747 / Net I/σ(I): 14.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
3-3.1140.44121331.1821100
3.11-3.2340.3120961.1031100
3.23-3.3840.20821121.2291100
3.38-3.5640.14921021.456199.9
3.56-3.783.90.10321181.7031100
3.78-4.073.90.07820892.016199.9
4.07-4.483.90.05621522.0841100
4.48-5.133.80.04721262.2941100
5.13-6.463.80.0521222.43199.9
6.46-503.70.03221952.068199.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.005data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1E8X

1e8x


Resolution: 3→20 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.884 / WRfactor Rfree: 0.238 / WRfactor Rwork: 0.201 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.799 / SU B: 23.592 / SU ML: 0.436 / SU R Cruickshank DPI: 0.391 / SU Rfree: 0.449 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.495 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.275 1064 5.1 %RANDOM
Rwork0.23 ---
obs0.233 20813 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 88.65 Å2 / Biso mean: 40.652 Å2 / Biso min: 24.74 Å2
Baniso -1Baniso -2Baniso -3
1--1.01 Å20 Å22.1 Å2
2--3.14 Å20 Å2
3----1.72 Å2
Refinement stepCycle: LAST / Resolution: 3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6812 0 34 0 6846
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0216996
X-RAY DIFFRACTIONr_bond_other_d0.0020.026400
X-RAY DIFFRACTIONr_angle_refined_deg1.1871.9589467
X-RAY DIFFRACTIONr_angle_other_deg0.82314917
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3735833
X-RAY DIFFRACTIONr_chiral_restr0.0640.21061
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.027595
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021393
X-RAY DIFFRACTIONr_nbd_refined0.1940.21970
X-RAY DIFFRACTIONr_nbd_other0.2060.27241
X-RAY DIFFRACTIONr_nbtor_other0.1180.25079
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1670.290
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1420.219
X-RAY DIFFRACTIONr_symmetry_vdw_other0.160.237
X-RAY DIFFRACTIONr_mcbond_it1.7782.54195
X-RAY DIFFRACTIONr_mcangle_it2.7956804
X-RAY DIFFRACTIONr_scbond_it1.7632.52801
X-RAY DIFFRACTIONr_scangle_it2.83152663
LS refinement shellResolution: 3→3.06 Å / Total num. of bins used: 25
RfactorNum. reflection
Rfree0.355 63
Rwork0.289 1166
all-1229
Refinement TLS params.Method: refined / Origin x: 34.5291 Å / Origin y: 47.2901 Å / Origin z: 27.3216 Å
111213212223313233
T0.3731 Å20.0339 Å20.0606 Å2-0.0112 Å20.0415 Å2--0.1698 Å2
L5.7761 °2-1.3628 °20.9284 °2-1.5911 °2-0.448 °2--3.2406 °2
S-0.136 Å °-0.0449 Å °-0.1803 Å °0.2369 Å °0.2432 Å °0.2934 Å °-0.599 Å °-0.2143 Å °-0.1071 Å °

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