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- PDB-3ml9: Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-046915... -

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Basic information

Entry
Database: PDB / ID: 3ml9
TitleDiscovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / phosphoinositide kinase / inhibition / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / regulation of calcium ion transmembrane transport / 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 / T cell chemotaxis ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / regulation of calcium ion transmembrane transport / 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 / 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 complex, class IA / 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 / 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 / ephrin receptor binding / T cell activation / 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-ML9 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsKnighton, D.R.
CitationJournal: ACS Med Chem Lett / Year: 2013
Title: Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.
Authors: Cheng, H. / Li, C. / Bailey, S. / Baxi, S.M. / Goulet, L. / Guo, L. / Hoffman, J. / Jiang, Y. / Johnson, T.O. / Johnson, T.W. / Knighton, D.R. / Li, J. / Liu, K.K. / Liu, Z. / Marx, M.A. / ...Authors: Cheng, H. / Li, C. / Bailey, S. / Baxi, S.M. / Goulet, L. / Guo, L. / Hoffman, J. / Jiang, Y. / Johnson, T.O. / Johnson, T.W. / Knighton, D.R. / Li, J. / Liu, K.K. / Liu, Z. / Marx, M.A. / Walls, M. / Wells, P.A. / Yin, M.J. / Zhu, J. / Zientek, M.
History
DepositionApr 16, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 9, 2014Group: Database references
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)111,1822
Polymers110,7561
Non-polymers4251
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)143.929, 67.294, 106.842
Angle α, β, γ (deg.)90.00, 95.46, 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 / PI3-kinase subunit gamma / PI3K-gamma / Phosphatidylinositol-4 / 5- ...PtdIns-3-kinase subunit gamma / PI3-kinase subunit gamma / PI3K-gamma / Phosphatidylinositol-4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p120-PI3K


Mass: 110756.164 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-ML9 / 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one


Mass: 425.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H27N5O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.33 Å3/Da / Density % sol: 47.1 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 7
Details: Protein] : [Compound] = 1:10 Hanging drop: 2.5ul protein + 2.5ul well @ 13 C Well solution: 0.1M Bis-Tris propane, pH8.2, 0.2M (NH4)2SO4, 16-18% (w/v) PEG3350, 10% (v/v) Ethylene Glycol and ...Details: Protein] : [Compound] = 1:10 Hanging drop: 2.5ul protein + 2.5ul well @ 13 C Well solution: 0.1M Bis-Tris propane, pH8.2, 0.2M (NH4)2SO4, 16-18% (w/v) PEG3350, 10% (v/v) Ethylene Glycol and 10mM TCEP, pH7.0 , VAPOR DIFFUSION, HANGING DROP, temperature 286K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 1, 2009 / Details: Mirrors
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.55→50 Å / Num. all: 34183 / Num. obs: 32831 / % possible obs: 99.6 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.7 % / Biso Wilson estimate: 46.9 Å2 / Rmerge(I) obs: 0.047 / Rsym value: 0.047 / Net I/σ(I): 28.8
Reflection shellResolution: 2.55→2.59 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.421 / Mean I/σ(I) obs: 2.24 / Num. unique all: 1705 / Rsym value: 0.421 / % possible all: 99.2

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
CNXrefinement
HKL-2000data reduction
HKL-2000data scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.55→44.79 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 150646.6 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.298 1578 4.9 %RANDOM
Rwork0.242 ---
all0.247 33291 --
obs0.245 32075 95.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 35.5839 Å2 / ksol: 0.335045 e/Å3
Displacement parametersBiso mean: 60.6 Å2
Baniso -1Baniso -2Baniso -3
1--5.69 Å20 Å28.6 Å2
2--12.09 Å20 Å2
3----6.4 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.49 Å0.37 Å
Luzzati d res low-5 Å
Luzzati sigma a0.41 Å0.4 Å
Refinement stepCycle: LAST / Resolution: 2.55→44.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6864 0 31 1 6896
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1
X-RAY DIFFRACTIONc_dihedral_angle_d22.7
X-RAY DIFFRACTIONc_improper_angle_d0.72
X-RAY DIFFRACTIONc_mcbond_it1.471.5
X-RAY DIFFRACTIONc_mcangle_it2.522
X-RAY DIFFRACTIONc_scbond_it1.962
X-RAY DIFFRACTIONc_scangle_it2.982.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.55→2.71 Å / Rfactor Rfree error: 0.028 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.42 230 4.7 %
Rwork0.366 4663 -
obs--88.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.pprotein.top
X-RAY DIFFRACTION2dna-rna_rep.pdna-rna.top
X-RAY DIFFRACTION3water_rep.parwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5lig.paramlig.top

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