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- PDB-5hkm: DISCOVERY OF NOVEL 7-AZAINDOLES AS PDK1 INHIBITORS -

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Basic information

Entry
Database: PDB / ID: 5hkm
TitleDISCOVERY OF NOVEL 7-AZAINDOLES AS PDK1 INHIBITORS
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE / PDK1 inhibitor
Function / homology
Function and homology information


3-phosphoinositide-dependent protein kinase activity / Activation of AKT2 / regulation of mast cell degranulation / negative regulation of toll-like receptor signaling pathway / type B pancreatic cell development / positive regulation of phospholipase activity / RSK activation / hyperosmotic response / regulation of canonical NF-kappaB signal transduction / positive regulation of vascular endothelial cell proliferation ...3-phosphoinositide-dependent protein kinase activity / Activation of AKT2 / regulation of mast cell degranulation / negative regulation of toll-like receptor signaling pathway / type B pancreatic cell development / positive regulation of phospholipase activity / RSK activation / hyperosmotic response / regulation of canonical NF-kappaB signal transduction / positive regulation of vascular endothelial cell proliferation / negative regulation of cardiac muscle cell apoptotic process / phospholipase activator activity / positive regulation of sprouting angiogenesis / Constitutive Signaling by AKT1 E17K in Cancer / CD28 dependent PI3K/Akt signaling / phospholipase binding / positive regulation of blood vessel endothelial cell migration / Role of LAT2/NTAL/LAB on calcium mobilization / Estrogen-stimulated signaling through PRKCZ / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of endothelial cell apoptotic process / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / extrinsic apoptotic signaling pathway / RHO GTPases activate PKNs / cellular response to epidermal growth factor stimulus / GPVI-mediated activation cascade / T cell costimulation / activation of protein kinase B activity / Integrin signaling / insulin-like growth factor receptor signaling pathway / positive regulation of release of sequestered calcium ion into cytosol / VEGFR2 mediated vascular permeability / VEGFR2 mediated cell proliferation / cell projection / calcium-mediated signaling / positive regulation of protein localization to plasma membrane / peptidyl-threonine phosphorylation / negative regulation of transforming growth factor beta receptor signaling pathway / negative regulation of protein kinase activity / epidermal growth factor receptor signaling pathway / CLEC7A (Dectin-1) signaling / FCERI mediated NF-kB activation / G beta:gamma signalling through PI3Kgamma / cellular response to insulin stimulus / positive regulation of angiogenesis / Regulation of TP53 Degradation / cell migration / Downstream TCR signaling / insulin receptor signaling pathway / PIP3 activates AKT signaling / cytoplasmic vesicle / actin cytoskeleton organization / protein autophosphorylation / postsynaptic density / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
PDK1-type, PH domain / PDPK1 family / PH domain / PH-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...PDK1-type, PH domain / PDPK1 family / PH domain / PH-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-61Y / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsWucherer-Plietker, M. / Esdar, C. / Knoechel, T. / Hillertz, P. / Heinrich, T. / Buchstaller, H.P. / Greiner, H. / Dorsch, D. / Calderini, M. / Bruge, D. ...Wucherer-Plietker, M. / Esdar, C. / Knoechel, T. / Hillertz, P. / Heinrich, T. / Buchstaller, H.P. / Greiner, H. / Dorsch, D. / Calderini, M. / Bruge, D. / Mueller, T.J.J. / Graedler, U.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Discovery of novel 7-azaindoles as PDK1 inhibitors.
Authors: Wucherer-Plietker, M. / Merkul, E. / Muller, T.J. / Esdar, C. / Knochel, T. / Heinrich, T. / Buchstaller, H.P. / Greiner, H. / Dorsch, D. / Finsinger, D. / Calderini, M. / Bruge, D. / Gradler, U.
History
DepositionJan 14, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jun 8, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 15, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3-phosphoinositide-dependent protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9254
Polymers35,4281
Non-polymers4973
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area240 Å2
ΔGint-15 kcal/mol
Surface area13380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)124.470, 124.470, 47.130
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein 3-phosphoinositide-dependent protein kinase 1 / hPDK1


Mass: 35427.609 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 51-359
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDPK1, PDK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O15530, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-61Y / 4-ethyl-6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-2-amine


Mass: 305.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15N7
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / 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: 3.35 Å3/Da / Density % sol: 63.33 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.6 / Details: 100 mM TRIS-HCl, 1.8 M NH4-sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Oct 22, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionNumber: 145555 / Rmerge(I) obs: 0.208 / Χ2: 1.23 / D res high: 2.1 Å / Num. obs: 23901 / % possible obs: 96.6
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)Num. obsIDRmerge(I) obs
6.2450100810.044
4.446.24171610.075
3.634.44218610.095
3.153.63256610.232
2.823.15292310.538
2.572.82320710.806
2.382.57344210.874
2.232.38352610.813
2.12.23332710.812
ReflectionResolution: 2.1→50 Å / Num. obs: 23901 / % possible obs: 96.6 % / Observed criterion σ(I): -3 / Redundancy: 6.1 % / Biso Wilson estimate: 17.37 Å2 / Rmerge F obs: 0.293 / Rmerge(I) obs: 0.2 / Rrim(I) all: 0.227 / Χ2: 1.234 / Net I/av σ(I): 8.02 / Net I/σ(I): 8.02 / Num. measured all: 145555
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
2.1-2.231.0160.81.149090396333270.98284
2.23-2.380.810.8131.4914183371635260.93294.9
2.38-2.570.6220.8741.8921681345434420.95399.7
2.57-2.820.530.8062.4924090320832070.866100
2.82-3.150.3170.5384.3321966292329230.578100
3.15-3.630.1450.2329.6719076256725660.249100
3.63-4.440.0610.09521.3316158218821860.10299.9
4.44-6.240.0470.07527.0812486171817160.08199.9
6.24-500.030.04437.296825101110080.04799.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
MOLREPphasing
PDB_EXTRACT3.15data extraction
XDSdata reduction
BUSTER2.11.6refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1OKZ

1okz


Resolution: 2.1→23.01 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.866 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.175 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.172 / SU Rfree Blow DPI: 0.188 / SU Rfree Cruickshank DPI: 0.191
RfactorNum. reflection% reflectionSelection details
Rfree0.273 10275 45.9 %RANDOM
Rwork0.19 ---
obs0.228 22386 90.5 %-
Displacement parametersBiso max: 124.41 Å2 / Biso mean: 34.68 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--1.0567 Å20 Å20 Å2
2---1.0567 Å20 Å2
3---2.1134 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.1→23.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2237 0 33 76 2346
Biso mean--44.54 29.01 -
Num. residues----273
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d812SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes52HARMONIC2
X-RAY DIFFRACTIONt_gen_planes329HARMONIC5
X-RAY DIFFRACTIONt_it2325HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion289SEMIHARMONIC5
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_contact2736SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2325HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3139HARMONIC21.16
X-RAY DIFFRACTIONt_omega_torsion3.01
X-RAY DIFFRACTIONt_other_torsion20.97
LS refinement shellResolution: 2.1→2.2 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.345 783 42.86 %
Rwork0.285 1044 -
all-1827 -
obs--55.78 %
Refinement TLS params.Method: refined / Origin x: 37.9905 Å / Origin y: -26.9657 Å / Origin z: -1.915 Å
111213212223313233
T-0.0393 Å2-0.0087 Å20.043 Å2--0.1166 Å20.015 Å2--0.0423 Å2
L1.3315 °2-0.0617 °20.3739 °2--0.0926 °20.2902 °2--1.7736 °2
S0.0548 Å °0.009 Å °0.1138 Å °-0.055 Å °-0.1285 Å °-0.1154 Å °0.0097 Å °0.0429 Å °0.0737 Å °
Refinement TLS groupSelection details: { A|* }

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