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- PDB-3l17: Discovery of (thienopyrimidin-2-yl)aminopyrimidines as Potent, Se... -

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Basic information

Entry
Database: PDB / ID: 3l17
TitleDiscovery 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
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 / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / 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-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 / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / T cell activation / ephrin receptor binding / positive regulation of endothelial cell migration / neutrophil chemotaxis / 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 / inflammatory response / immune 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-JZY / 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 / 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)111,2322
Polymers110,7271
Non-polymers5051
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)144.095, 67.727, 107.455
Angle α, β, γ (deg.)90.000, 96.070, 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: 110727.102 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-JZY / 4-methyl-5-(6-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-4-morpholin-4-ylthieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine


Mass: 504.629 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N8O3S2

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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: 2.35 Å3/Da / Density % sol: 47.76 %
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: Jun 9, 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: 20541 / % possible obs: 97.8 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.074 / Χ2: 0.968 / Net I/σ(I): 12.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
3-3.112.70.36217400.595183.1
3.11-3.233.10.29919930.707195.8
3.23-3.383.60.24420620.85199.6
3.38-3.563.70.18220891.0431100
3.56-3.783.80.1320911.1991100
3.78-4.073.70.09620701.1511100
4.07-4.483.70.07821161.081100
4.48-5.133.70.07420981.021100
5.13-6.463.70.07321051.0341100
6.46-503.60.0521770.734199.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMAC5.2.0019refinement
PDB_EXTRACT3.005data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1E8X

1e8x


Resolution: 3→45.18 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.911 / Occupancy max: 1 / Occupancy min: 1 / SU B: 50.742 / SU ML: 0.403 / 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
Rfree0.271 1042 5.1 %RANDOM
Rwork0.216 ---
obs0.218 20480 97.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 127.55 Å2 / Biso mean: 101.362 Å2 / Biso min: 88.33 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å21.84 Å2
2--2.01 Å20 Å2
3----1.6 Å2
Refinement stepCycle: LAST / Resolution: 3→45.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6820 0 34 0 6854
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0227005
X-RAY DIFFRACTIONr_bond_other_d0.0010.024808
X-RAY DIFFRACTIONr_angle_refined_deg1.3161.9659480
X-RAY DIFFRACTIONr_angle_other_deg0.885311730
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.635833
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.48824.286329
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.689151271
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5151542
X-RAY DIFFRACTIONr_chiral_restr0.070.21061
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.027618
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021394
X-RAY DIFFRACTIONr_nbd_refined0.2410.21882
X-RAY DIFFRACTIONr_nbd_other0.1980.25147
X-RAY DIFFRACTIONr_nbtor_refined0.190.23446
X-RAY DIFFRACTIONr_nbtor_other0.0880.23837
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1740.2163
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.1910.22
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1430.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1160.211
X-RAY DIFFRACTIONr_mcbond_it0.5521.55434
X-RAY DIFFRACTIONr_mcbond_other0.0641.51682
X-RAY DIFFRACTIONr_mcangle_it0.6526810
X-RAY DIFFRACTIONr_scbond_it0.87933289
X-RAY DIFFRACTIONr_scangle_it1.3574.52670
LS refinement shellResolution: 3→3.062 Å / Total num. of bins used: 25
RfactorNum. reflection% reflection
Rfree0.408 48 -
Rwork0.319 961 -
all-1009 -
obs--80.72 %
Refinement TLS params.Method: refined / Origin x: 34.1085 Å / Origin y: 47.9436 Å / Origin z: 27.2701 Å
111213212223313233
T-0.264 Å2-0.0252 Å20.1109 Å2--0.454 Å2-0.0094 Å2---0.4068 Å2
L3.9024 °2-1.0246 °20.8536 °2-1.4668 °2-0.0819 °2--2.1678 °2
S-0.0866 Å °0.1139 Å °0.0185 Å °0.1466 Å °0.0586 Å °0.1942 Å °-0.3557 Å °-0.0124 Å °0.028 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A143 - 1091
2X-RAY DIFFRACTION1A1

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