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- PDB-5oq4: PQR309 - a Potent, Brain-Penetrant, Orally Bioavailable, pan-Clas... -

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Basic information

Entry
Database: PDB / ID: 5oq4
TitlePQR309 - a Potent, Brain-Penetrant, Orally Bioavailable, pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / PI3K / 3-kinase / lipid kinase / kinase / inhibitor / PQR309 / NCB5
Function / homology
Function and homology information


negative regulation of triglyceride catabolic process / secretory granule localization / 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 triglyceride catabolic process / secretory granule localization / 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 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / mast cell degranulation / 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-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / phosphorylation / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / ephrin receptor binding / neutrophil chemotaxis / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of endothelial cell migration / T cell activation / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / kinase activity / phospholipase C-activating G protein-coupled receptor signaling pathway / 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 / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / identical protein binding / membrane / 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. / 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 / 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-A3W / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsWilliams, R.L. / Zhang, X.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_U105184308 United Kingdom
CitationJournal: J. Med. Chem. / Year: 2017
Title: 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology.
Authors: Beaufils, F. / Cmiljanovic, N. / Cmiljanovic, V. / Bohnacker, T. / Melone, A. / Marone, R. / Jackson, E. / Zhang, X. / Sele, A. / Borsari, C. / Mestan, J. / Hebeisen, P. / Hillmann, P. / ...Authors: Beaufils, F. / Cmiljanovic, N. / Cmiljanovic, V. / Bohnacker, T. / Melone, A. / Marone, R. / Jackson, E. / Zhang, X. / Sele, A. / Borsari, C. / Mestan, J. / Hebeisen, P. / Hillmann, P. / Giese, B. / Zvelebil, M. / Fabbro, D. / Williams, R.L. / Rageot, D. / Wymann, M.P.
History
DepositionAug 10, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 6, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 17, 2024Group: 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

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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)111,3604
Polymers110,7561
Non-polymers6043
Water64936
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering, The mass as measured by MALS is consistent with a monomer of 144-1102 p110gamma
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area390 Å2
ΔGint-28 kcal/mol
Surface area36660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.490, 67.360, 103.610
Angle α, β, γ (deg.)90.00, 96.94, 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 gamma isoform / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 110756.164 Da / Num. of mol.: 1 / Mutation: residues 1-143 truncated
Source method: isolated from a genetically manipulated source
Details: PI3K gamma with residues 1-143 truncated / Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A3W / 5-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine / PQR309


Mass: 411.382 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20F3N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 36 / 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: 2.2 Å3/Da / Density % sol: 44 %
Crystal growTemperature: 290.15 K / Method: vapor diffusion / pH: 7.5 / Details: 16% PEG 4000, 250mM (NH4)2SO4 and 100mM Tris pH7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.00715 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 9, 2009 / Details: Bent cylindrical mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00715 Å / Relative weight: 1
ReflectionResolution: 2.7→61 Å / Num. obs: 24608 / % possible obs: 97 % / Redundancy: 3.4 % / Biso Wilson estimate: 50.65 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.04 / Net I/σ(I): 12.6
Reflection shellResolution: 2.7→2.85 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 3581 / CC1/2: 0.809 / Rpim(I) all: 0.308 / % possible all: 92.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1E8Y

1e8y


Resolution: 2.7→61 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.904 / SU B: 32.364 / SU ML: 0.304 / Cross valid method: THROUGHOUT / ESU R Free: 0.389 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26422 1292 5 %RANDOM
Rwork0.19643 ---
obs0.19981 24405 96.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 64.057 Å2
Baniso -1Baniso -2Baniso -3
1--4.58 Å20 Å20.61 Å2
2--1.3 Å20 Å2
3---3.04 Å2
Refinement stepCycle: 1 / Resolution: 2.7→61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6769 0 39 36 6844
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0196960
X-RAY DIFFRACTIONr_bond_other_d0.0030.026548
X-RAY DIFFRACTIONr_angle_refined_deg1.981.9659415
X-RAY DIFFRACTIONr_angle_other_deg1.255315193
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5115825
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.07924.22327
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.074151263
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.471542
X-RAY DIFFRACTIONr_chiral_restr0.1120.21057
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0217531
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021399
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.0034.4633327
X-RAY DIFFRACTIONr_mcbond_other3.0024.4623326
X-RAY DIFFRACTIONr_mcangle_it4.9546.6714140
X-RAY DIFFRACTIONr_mcangle_other4.9546.6724141
X-RAY DIFFRACTIONr_scbond_it3.0434.7543633
X-RAY DIFFRACTIONr_scbond_other3.0184.7413622
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.946.9855263
X-RAY DIFFRACTIONr_long_range_B_refined9.67182.58929288
X-RAY DIFFRACTIONr_long_range_B_other9.67182.58829286
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 87 -
Rwork0.287 1734 -
obs--92.11 %
Refinement TLS params.Method: refined / Origin x: 31.749 Å / Origin y: 0.188 Å / Origin z: 25.832 Å
111213212223313233
T0.1305 Å2-0.0092 Å20.0741 Å2-0.0061 Å2-0.0163 Å2--0.0949 Å2
L1.7795 °20.3249 °20.3251 °2-0.3347 °2-0.1795 °2--0.7776 °2
S0.0017 Å °0.013 Å °-0.1773 Å °0.0448 Å °0.0315 Å °-0.079 Å °-0.116 Å °0.0103 Å °-0.0332 Å °

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