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- PDB-4uwg: Discovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-o... -

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Basic information

Entry
Database: PDB / ID: 4uwg
TitleDiscovery of (2S)-8-((3R)-3-Methylmorpholin-4-yl)-1-(3-methyl-2-oxo- butyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido(1,2-a)pyrimidin-6- one: a Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors
ComponentsPHOSPHATIDYLINOSITOL 3-KINASE CATALYTIC SUBUNIT TYPE 3
KeywordsTRANSFERASE
Function / homology
Function and homology information


Toll Like Receptor 9 (TLR9) Cascade / postsynaptic endosome / Synthesis of PIPs at the late endosome membrane / phosphatidylinositol 3-kinase complex, class III / Synthesis of PIPs at the early endosome membrane / phosphatidylinositol 3-kinase complex, class III, type II / phosphatidylinositol 3-kinase complex, class III, type I / presynaptic endosome / positive regulation of protein lipidation / positive regulation by host of viral genome replication ...Toll Like Receptor 9 (TLR9) Cascade / postsynaptic endosome / Synthesis of PIPs at the late endosome membrane / phosphatidylinositol 3-kinase complex, class III / Synthesis of PIPs at the early endosome membrane / phosphatidylinositol 3-kinase complex, class III, type II / phosphatidylinositol 3-kinase complex, class III, type I / presynaptic endosome / positive regulation of protein lipidation / positive regulation by host of viral genome replication / Synthesis of PIPs at the Golgi membrane / phosphatidylinositol kinase activity / protein localization to phagophore assembly site / protein targeting to lysosome / early endosome to late endosome transport / pexophagy / phagophore assembly site / Translation of Replicase and Assembly of the Replication Transcription Complex / phosphatidylinositol-3-phosphate biosynthetic process / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / Macroautophagy / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / autolysosome / synaptic vesicle endocytosis / PI3K Cascade / axoneme / autophagosome assembly / RHO GTPases Activate NADPH Oxidases / autophagosome maturation / regulation of macroautophagy / cellular response to glucose starvation / autophagosome / regulation of cytokinesis / GABA-ergic synapse / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / macroautophagy / autophagy / phagocytic vesicle membrane / endocytosis / late endosome / peroxisome / Translation of Replicase and Assembly of the Replication Transcription Complex / midbody / protein kinase activity / endosome / regulation of autophagy / cell division / SARS-CoV-2 activates/modulates innate and adaptive immune responses / glutamatergic synapse / ATP binding / membrane / cytosol / cytoplasm
Similarity search - Function
Phosphatidylinositol 3-kinase, Vps34 type / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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 ...Phosphatidylinositol 3-kinase, Vps34 type / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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 3/4-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 / C2 domain superfamily / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Armadillo-type fold / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-RBQ / Phosphatidylinositol 3-kinase catalytic subunit type 3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsPasquier, B. / El-Ahmad, Y. / Filoche-Romme, B. / Dureuil, C. / Fassy, F. / Abecassis, P.Y. / Mathieu, M. / Bertrand, T. / Benard, T. / Barriere, C. ...Pasquier, B. / El-Ahmad, Y. / Filoche-Romme, B. / Dureuil, C. / Fassy, F. / Abecassis, P.Y. / Mathieu, M. / Bertrand, T. / Benard, T. / Barriere, C. / ElBatti, S. / Letallec, J.P. / Sonnefraud, V. / Brollo, M. / Delbarre, L. / Loyau, V. / Pilorge, F. / Bertin, L. / Richepin, P. / Arigon, J. / Labrosse, J.R. / Clement, J. / Durand, F. / Combet, R. / Perraut, P. / Leroy, V. / Gay, F. / Lefrancois, D. / Bretin, F. / Marquette, J.P. / Michot, N. / Caron, A. / Castell, C. / Schio, L. / McCort, G. / Goulaouic, H. / Garcia-Echeverria, C. / Ronan, B.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-Yl]-1-(3-Methyl-2-Oxobutyl)-2-(Trifluoromethyl)-3,4-Dihydro-2H-Pyrimido[1,2-A]Pyrimidin-6-One: A Novel Potent and Selective Inhibitor of Vps34 for ...Title: Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-Yl]-1-(3-Methyl-2-Oxobutyl)-2-(Trifluoromethyl)-3,4-Dihydro-2H-Pyrimido[1,2-A]Pyrimidin-6-One: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors.
Authors: Pasquier, B. / El-Ahmad, Y. / Filoche-Romme, B. / Dureuil, C. / Fassy, F. / Abecassis, P. / Mathieu, M. / Bertrand, T. / Benard, T. / Barriere, C. / El Batti, S. / Letallec, J. / Sonnefraud, ...Authors: Pasquier, B. / El-Ahmad, Y. / Filoche-Romme, B. / Dureuil, C. / Fassy, F. / Abecassis, P. / Mathieu, M. / Bertrand, T. / Benard, T. / Barriere, C. / El Batti, S. / Letallec, J. / Sonnefraud, V. / Brollo, M. / Delbarre, L. / Loyau, V. / Pilorge, F. / Bertin, L. / Richepin, P. / Arigon, J. / Labrosse, J. / Clement, J. / Durand, F. / Combet, R. / Perraut, P. / Leroy, V. / Gay, F. / Lefrancois, D. / Bretin, F. / Marquette, J. / Michot, N. / Caron, A. / Castell, C. / Schio, L. / Mccort, G. / Goulaouic, H. / Garcia-Echeverria, C. / Ronan, B.
History
DepositionAug 12, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 26, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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 3-KINASE CATALYTIC SUBUNIT TYPE 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,2765
Polymers68,5971
Non-polymers6794
Water95553
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)93.800, 147.010, 61.780
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein PHOSPHATIDYLINOSITOL 3-KINASE CATALYTIC SUBUNIT TYPE 3 / PI3-KINASE TYPE 3 / PI3K TYPE 3 / PTDINS-3-KINASE TYPE 3 / PHO SPHATIDYLINOSITOL 3-KINASE P100 ...PI3-KINASE TYPE 3 / PI3K TYPE 3 / PTDINS-3-KINASE TYPE 3 / PHO SPHATIDYLINOSITOL 3-KINASE P100 SUBUNIT / PHOSPHOINOSITIDE-3-KINASE CLASS 3 / HVPS34 / PHOSPHOINOSITIDE 3-KINASE


Mass: 68597.391 Da / Num. of mol.: 1
Fragment: VPS34 HELICAL AND KINASE DOMAINS, RESIDUES 282-879
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q8NEB9, phosphatidylinositol 3-kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-RBQ / (8S)-2-(morpholin-4-yl)-9-[2-(propan-2-yloxy)ethyl]-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one


Mass: 390.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H25F3N4O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 3.41 Å3/Da / Density % sol: 63.9 % / Description: NONE
Crystal growpH: 8.5 / Details: AMMONIUM SULFATE 2M - TRIS 100MM PH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.98011
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 12, 2013 / Details: KIRKPATRICK-BAEZ PAIR OF BI-MORPH MIRRORS
RadiationMonochromator: SI (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98011 Å / Relative weight: 1
ReflectionResolution: 2.7→49 Å / Num. obs: 24128 / % possible obs: 99.2 % / Observed criterion σ(I): 3 / Redundancy: 6.4 % / Biso Wilson estimate: 63.61 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 14.2
Reflection shellResolution: 2.7→2.83 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.63 / Mean I/σ(I) obs: 2.5 / % possible all: 92.9

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4UWF

4uwf


Resolution: 2.7→46.88 Å / Cor.coef. Fo:Fc: 0.9132 / Cor.coef. Fo:Fc free: 0.8941 / SU R Cruickshank DPI: 0.42 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.422 / SU Rfree Blow DPI: 0.255 / SU Rfree Cruickshank DPI: 0.258
RfactorNum. reflection% reflectionSelection details
Rfree0.2211 1229 5.11 %RANDOM
Rwork0.1803 ---
obs0.1823 24071 99.5 %-
Displacement parametersBiso mean: 62.47 Å2
Baniso -1Baniso -2Baniso -3
1--16.3916 Å20 Å20 Å2
2---9.5753 Å20 Å2
3---25.9669 Å2
Refine analyzeLuzzati coordinate error obs: 0.332 Å
Refinement stepCycle: LAST / Resolution: 2.7→46.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4403 0 42 53 4498
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014542HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.116146HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1648SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes129HARMONIC2
X-RAY DIFFRACTIONt_gen_planes640HARMONIC5
X-RAY DIFFRACTIONt_it4542HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.55
X-RAY DIFFRACTIONt_other_torsion21.18
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion579SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5122SEMIHARMONIC4
LS refinement shellResolution: 2.7→2.82 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2538 147 5.24 %
Rwork0.2232 2657 -
all0.2247 2804 -
obs--99.5 %

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