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- PDB-5kcv: Crystal structure of allosteric inhibitor, ARQ 092, in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5kcv
TitleCrystal structure of allosteric inhibitor, ARQ 092, in complex with autoinhibited form of AKT1
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE/INHIBITOR / AKT / Allosteric inhibitor / Kinase inhibitor / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of tRNA methylation / negative regulation of protein maturation / response to insulin-like growth factor stimulus / mammalian oogenesis stage / regulation of glycogen biosynthetic process / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / negative regulation of protein localization to lysosome / maintenance of protein location in mitochondrion / cellular response to decreased oxygen levels ...regulation of tRNA methylation / negative regulation of protein maturation / response to insulin-like growth factor stimulus / mammalian oogenesis stage / regulation of glycogen biosynthetic process / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / negative regulation of protein localization to lysosome / maintenance of protein location in mitochondrion / cellular response to decreased oxygen levels / cellular response to rapamycin / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / maternal placenta development / establishment of protein localization to mitochondrion / activation-induced cell death of T cells / potassium channel activator activity / AKT phosphorylates targets in the nucleus / negative regulation of fatty acid beta-oxidation / negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway / cellular response to oxidised low-density lipoprotein particle stimulus / negative regulation of cilium assembly / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / positive regulation of glucose metabolic process / cellular response to peptide / positive regulation of TORC2 signaling / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / interleukin-18-mediated signaling pathway / response to fluid shear stress / fibroblast migration / MTOR signalling / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / response to growth factor / complement receptor mediated signaling pathway / RAB GEFs exchange GTP for GDP on RABs / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / glycogen biosynthetic process / peripheral nervous system myelin maintenance / positive regulation of protein localization to cell surface / sphingosine-1-phosphate receptor signaling pathway / positive regulation of endodeoxyribonuclease activity / phosphorylation / cell migration involved in sprouting angiogenesis / response to growth hormone / anoikis / regulation of postsynapse organization / AKT phosphorylates targets in the cytosol / TORC2 complex binding / positive regulation of fibroblast migration / regulation of myelination / labyrinthine layer blood vessel development / response to UV-A / Regulation of TP53 Activity through Association with Co-factors / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / KSRP (KHSRP) binds and destabilizes mRNA / execution phase of apoptosis / response to food / negative regulation of macroautophagy / Co-inhibition by CTLA4 / negative regulation of cGAS/STING signaling pathway / cellular response to stress / negative regulation of release of cytochrome c from mitochondria / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of PERK-mediated unfolded protein response / positive regulation of protein metabolic process / apoptotic mitochondrial changes / phosphatidylinositol-3,4,5-trisphosphate binding / TOR signaling / behavioral response to pain / Regulation of localization of FOXO transcription factors / peptidyl-threonine phosphorylation / protein serine/threonine kinase inhibitor activity / positive regulation of peptidyl-serine phosphorylation / cellular response to vascular endothelial growth factor stimulus / negative regulation of Notch signaling pathway / CD28 dependent PI3K/Akt signaling / positive regulation of blood vessel endothelial cell migration / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Activation of BAD and translocation to mitochondria / positive regulation of fat cell differentiation / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of G1/S transition of mitotic cell cycle / Mitochondrial unfolded protein response (UPRmt) / positive regulation of glycogen biosynthetic process / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / vascular endothelial cell response to laminar fluid shear stress / positive regulation of lipid biosynthetic process / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Cyclin E associated events during G1/S transition / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Cyclin A:Cdk2-associated events at S phase entry / Downregulation of ERBB2:ERBB3 signaling / eNOS activation
Similarity search - Function
Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain ...Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily / Roll / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-6S1 / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsEathiraj, S.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor.
Authors: Lapierre, J.M. / Eathiraj, S. / Vensel, D. / Liu, Y. / Bull, C.O. / Cornell-Kennon, S. / Iimura, S. / Kelleher, E.W. / Kizer, D.E. / Koerner, S. / Makhija, S. / Matsuda, A. / Moussa, M. / ...Authors: Lapierre, J.M. / Eathiraj, S. / Vensel, D. / Liu, Y. / Bull, C.O. / Cornell-Kennon, S. / Iimura, S. / Kelleher, E.W. / Kizer, D.E. / Koerner, S. / Makhija, S. / Matsuda, A. / Moussa, M. / Namdev, N. / Savage, R.E. / Szwaya, J. / Volckova, E. / Westlund, N. / Wu, H. / Schwartz, B.
History
DepositionJun 7, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 29, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 27, 2016Group: Database references
Revision 1.2Sep 27, 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 / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RAC-alpha serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,9912
Polymers53,5581
Non-polymers4331
Water1,42379
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.720, 87.620, 128.790
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein RAC-alpha serine/threonine-protein kinase / Protein kinase B / PKB / Protein kinase B alpha / PKB alpha / Proto-oncogene c-Akt / RAC-PK-alpha


Mass: 53558.012 Da / Num. of mol.: 1 / Mutation: E114A, E115A, E116A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT1, PKB, RAC / Cell line (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P31749, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-6S1 / 3-[3-[4-(1-azanylcyclobutyl)phenyl]-5-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine


Mass: 432.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H24N6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.36 Å3/Da / Density % sol: 47.78 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 16% butanol, 10mM ammonium sulfate, 0.1% 2-mercaptoethanol, 15% ethylene glycol, 50mM Tris, pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.0928 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 15, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0928 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 13431 / % possible obs: 92.7 % / Redundancy: 12 % / Rmerge(I) obs: 0.055 / Net I/σ(I): 25.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
MOSFLMv1.0data reduction
SCALAv1.0data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1MRV, 2UVM

1mrv

2uvm


Resolution: 2.7→8 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.904 / SU B: 13.927 / SU ML: 0.285 / Cross valid method: THROUGHOUT / ESU R: 1.324 / ESU R Free: 0.376 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2686 638 5 %RANDOM
Rwork0.20961 ---
obs0.21271 12090 87.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 67.735 Å2
Baniso -1Baniso -2Baniso -3
1--0.31 Å2-0 Å2-0 Å2
2---1.7 Å2-0 Å2
3---2.01 Å2
Refinement stepCycle: LAST / Resolution: 2.7→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2762 0 33 79 2874
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0192874
X-RAY DIFFRACTIONr_bond_other_d0.0020.022670
X-RAY DIFFRACTIONr_angle_refined_deg1.5261.9623908
X-RAY DIFFRACTIONr_angle_other_deg0.8743.0036117
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6725347
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.77623.692130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.77615430
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0661513
X-RAY DIFFRACTIONr_chiral_restr0.0810.2420
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213242
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02692
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_it5.2936.6991406
X-RAY DIFFRACTIONr_mcbond_other5.2956.6971405
X-RAY DIFFRACTIONr_mcangle_it7.6910.0421747
X-RAY DIFFRACTIONr_mcangle_other7.68910.0431748
X-RAY DIFFRACTIONr_scbond_it5.2556.8931468
X-RAY DIFFRACTIONr_scbond_other5.2536.8921469
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.82410.2422160
X-RAY DIFFRACTIONr_long_range_B_refined11.88862.69911491
X-RAY DIFFRACTIONr_long_range_B_other11.88762.69711492
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.762 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.318 37 -
Rwork0.333 752 -
obs--83.49 %

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