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- PDB-4ejn: Crystal structure of autoinhibited form of AKT1 in complex with N... -

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Entry
Database: PDB / ID: 4ejn
TitleCrystal structure of autoinhibited form of AKT1 in complex with N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-3-fluorobenzamide
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Akt1 / autoinhibition / allosteric inhibitor / kinase inhibitor / hydrophobic collapase / Kinase / ATPase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of endodeoxyribonuclease activity / regulation of tRNA methylation / negative regulation of protein maturation / negative regulation of fatty acid beta-oxidation / positive regulation of protein localization to endoplasmic reticulum / regulation of glycogen biosynthetic process / negative regulation of lymphocyte migration / cellular response to rapamycin / negative regulation of protein localization to lysosome / maintenance of protein location in mitochondrion ...positive regulation of endodeoxyribonuclease activity / regulation of tRNA methylation / negative regulation of protein maturation / negative regulation of fatty acid beta-oxidation / positive regulation of protein localization to endoplasmic reticulum / regulation of glycogen biosynthetic process / negative regulation of lymphocyte migration / cellular response to rapamycin / negative regulation of protein localization to lysosome / maintenance of protein location in mitochondrion / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / regulation of type B pancreatic cell development / positive regulation of anaphase-promoting complex-dependent catabolic process / activation-induced cell death of T cells / : / potassium channel activator activity / mammary gland epithelial cell differentiation / AKT phosphorylates targets in the nucleus / fibroblast migration / cellular response to oxidised low-density lipoprotein particle stimulus / negative regulation of cilium assembly / negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / positive regulation of TORC2 signaling / positive regulation of glucose metabolic process / RUNX2 regulates genes involved in cell migration / beta-arrestin-dependent dopamine receptor signaling pathway / interleukin-18-mediated signaling pathway / positive regulation of protein localization to cell surface / MTOR signalling / response to growth factor / cell migration involved in sprouting angiogenesis / response to fluid shear stress / negative regulation of leukocyte cell-cell adhesion / RAB GEFs exchange GTP for GDP on RABs / glycogen biosynthetic process / phosphatidylinositol-3,4-bisphosphate binding / complement receptor mediated signaling pathway / sphingosine-1-phosphate receptor signaling pathway / response to growth hormone / AKT phosphorylates targets in the cytosol / anoikis / regulation of postsynapse organization / regulation of neuron projection development / KSRP (KHSRP) binds and destabilizes mRNA / response to UV-A / Regulation of TP53 Activity through Association with Co-factors / TORC2 complex binding / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / negative regulation of macroautophagy / Co-inhibition by CTLA4 / cellular response to stress / negative regulation of release of cytochrome c from mitochondria / negative regulation of cGAS/STING signaling pathway / peptidyl-threonine phosphorylation / negative regulation of PERK-mediated unfolded protein response / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of protein metabolic process / phosphatidylinositol-3,4,5-trisphosphate binding / Regulation of localization of FOXO transcription factors / negative regulation of Notch signaling pathway / behavioral response to pain / TOR signaling / CD28 dependent PI3K/Akt signaling / positive regulation of peptidyl-serine phosphorylation / Activation of BAD and translocation to mitochondria / positive regulation of blood vessel endothelial cell migration / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of glycogen biosynthetic process / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Mitochondrial unfolded protein response (UPRmt) / positive regulation of fat cell differentiation / positive regulation of lipid biosynthetic process / protein serine/threonine kinase inhibitor activity / response to insulin-like growth factor stimulus / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / T cell costimulation / positive regulation of G1/S transition of mitotic cell cycle / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Cyclin E associated events during G1/S transition / vascular endothelial cell response to laminar fluid shear stress / Cyclin A:Cdk2-associated events at S phase entry / Regulation of TP53 Activity through Acetylation / nitric oxide metabolic process / nitric oxide biosynthetic process / negative regulation of proteolysis / eNOS activation / Integrin signaling / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / regulation of mRNA stability / positive regulation of endothelial cell proliferation / insulin-like growth factor receptor signaling pathway / 14-3-3 protein binding / protein serine/threonine/tyrosine kinase activity / positive regulation of TORC1 signaling / negative regulation of protein ubiquitination / regulation of cell migration / FLT3 Signaling
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-0R4 / 2-BUTANOL / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsEathiraj, S.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors.
Authors: Ashwell, M.A. / Lapierre, J.M. / Brassard, C. / Bresciano, K. / Bull, C. / Cornell-Kennon, S. / Eathiraj, S. / France, D.S. / Hall, T. / Hill, J. / Kelleher, E. / Khanapurkar, S. / Kizer, D. ...Authors: Ashwell, M.A. / Lapierre, J.M. / Brassard, C. / Bresciano, K. / Bull, C. / Cornell-Kennon, S. / Eathiraj, S. / France, D.S. / Hall, T. / Hill, J. / Kelleher, E. / Khanapurkar, S. / Kizer, D. / Koerner, S. / Link, J. / Liu, Y. / Makhija, S. / Moussa, M. / Namdev, N. / Nguyen, K. / Nicewonger, R. / Palma, R. / Szwaya, J. / Tandon, M. / Uppalapati, U. / Vensel, D. / Volak, L.P. / Volckova, E. / Westlund, N. / Wu, H. / Yang, R.Y. / Chan, T.C.
History
DepositionApr 6, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 23, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)52,4544
Polymers51,7461
Non-polymers7083
Water2,972165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.508, 88.214, 126.936
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: 51746.035 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 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P31749, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-0R4 / N-(4-{5-[3-(acetylamino)phenyl]-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl}benzyl)-3-fluorobenzamide


Mass: 571.604 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H26FN7O2
#3: Chemical ChemComp-SBT / 2-BUTANOL


Mass: 74.122 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 165 / 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

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Sample preparation

CrystalDensity Matthews: 2.41 Å3/Da / Density % sol: 48.92 %
Crystal growTemperature: 277 K / Method: evaporation / pH: 7.5
Details: 16% butanol, 10mM ammonium sulfate, 0.1% 2-mercaptoethanol, 15% ethylene glycol, 50mM Tris , pH 7.5, EVAPORATION, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 15, 2010
RadiationMonochromator: Double silicon(111) crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.19→50 Å / Num. all: 26366 / Num. obs: 26311 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Rsym value: 0.046
Reflection shellResolution: 2.19→2.23 Å / % possible all: 99.6

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
REFMAC5.5.0102refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.19→10 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.915 / SU B: 7.161 / SU ML: 0.184 / Cross valid method: THROUGHOUT / ESU R: 0.271 / ESU R Free: 0.22 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27596 1317 5.1 %RANDOM
Rwork0.2373 ---
obs0.23939 24706 99.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.084 Å2
Baniso -1Baniso -2Baniso -3
1--0.68 Å20 Å20 Å2
2---0.67 Å20 Å2
3---1.35 Å2
Refinement stepCycle: LAST / Resolution: 2.19→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2939 0 52 165 3156
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0223072
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2681.9674167
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.925371
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.51423.91133
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.73915479
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1031512
X-RAY DIFFRACTIONr_chiral_restr0.0790.2449
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212343
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.6261.51866
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.18422969
X-RAY DIFFRACTIONr_scbond_it1.51731206
X-RAY DIFFRACTIONr_scangle_it2.5944.51198
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.192→2.246 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.357 92 -
Rwork0.305 1707 -
obs--97.82 %

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