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- PDB-5ho7: DISCOVERY OF NOVEL 7-AZAINDOLES AS PDK1 INHIBITORS -

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Basic information

Entry
Database: PDB / ID: 5ho7
TitleDISCOVERY OF NOVEL 7-AZAINDOLES AS PDK1 INHIBITORS
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE / PDK1 inhibitor
Function / homology
Function and homology information


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 ...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 / phospholipase binding / CD28 dependent PI3K/Akt signaling / positive regulation of blood vessel endothelial cell migration / Role of LAT2/NTAL/LAB on calcium mobilization / Estrogen-stimulated signaling through PRKCZ / vascular endothelial cell response to laminar fluid shear stress / negative regulation of endothelial cell apoptotic process / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / activation of protein kinase B activity / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / GPVI-mediated activation cascade / extrinsic apoptotic signaling pathway / T cell costimulation / Integrin signaling / peptidyl-threonine phosphorylation / cellular response to epidermal growth factor stimulus / insulin-like growth factor receptor signaling pathway / positive regulation of release of sequestered calcium ion into cytosol / VEGFR2 mediated cell proliferation / VEGFR2 mediated vascular permeability / cell projection / positive regulation of protein localization to plasma membrane / phosphatidylinositol 3-kinase/protein kinase B signal transduction / negative regulation of transforming growth factor beta receptor signaling pathway / calcium-mediated signaling / CLEC7A (Dectin-1) signaling / epidermal growth factor receptor signaling pathway / FCERI mediated NF-kB activation / cellular response to insulin stimulus / positive regulation of angiogenesis / G beta:gamma signalling through PI3Kgamma / Regulation of TP53 Degradation / insulin receptor signaling pathway / Downstream TCR signaling / cell migration / PIP3 activates AKT signaling / actin cytoskeleton organization / protein autophosphorylation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cytoplasmic vesicle / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / postsynaptic density / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PDK1-type, PH domain / PH domain / PDPK1 family / : / PH-like domain superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site ...PDK1-type, PH domain / PH domain / PDPK1 family / : / PH-like domain superfamily / 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 Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-63L / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 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 19, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jun 8, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 15, 2016Group: Database references
Revision 1.2Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Nov 20, 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: 3-phosphoinositide-dependent protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7393
Polymers35,4281
Non-polymers3112
Water28816
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-16 kcal/mol
Surface area13970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)124.050, 124.050, 47.220
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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-63L / 5-amino-3-(methylsulfanyl)-1H-pyrazole-1,4-dicarboxamide / 5-Amino-3-methylsulfanyl-pyrazole-1,4-dicarboxylicacid diamide


Mass: 215.233 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H9N5O2S
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / 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: 2.96 Å3/Da / Density % sol: 58.45 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.6 / Details: 100 mM Tris-HCl, 1.8 M NH4-sulfate / PH range: 8.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Mar 10, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→43.23 Å / Num. obs: 7852 / % possible obs: 91.2 % / Redundancy: 2.1 % / Biso Wilson estimate: 70.42 Å2 / Rmerge(I) obs: 0.075 / Net I/σ(I): 11

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1OKZ

1okz


Resolution: 3→43.23 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.882 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.385
RfactorNum. reflection% reflectionSelection details
Rfree0.233 362 4.62 %RANDOM
Rwork0.173 ---
obs0.175 7841 91.4 %-
Displacement parametersBiso mean: 64.63 Å2
Baniso -1Baniso -2Baniso -3
1--10.0608 Å20 Å20 Å2
2---10.0608 Å20 Å2
3---20.1215 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: LAST / Resolution: 3→43.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2304 0 34 20 2358
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012394HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.143235HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d839SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes54HARMONIC2
X-RAY DIFFRACTIONt_gen_planes338HARMONIC5
X-RAY DIFFRACTIONt_it2394HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.78
X-RAY DIFFRACTIONt_other_torsion21.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion294SEMIHARMONIC5
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_contact2748SEMIHARMONIC4
LS refinement shellHighest resolution: 3 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.31 -4.49 %
Rwork0.212 1766 -
obs--76.88 %
Refinement TLS params.Method: refined / Origin x: 42.3316 Å / Origin y: 18.8619 Å / Origin z: 13.5198 Å
111213212223313233
T-0.1076 Å2-0.005 Å2-0.0265 Å2--0.1868 Å20.0632 Å2---0.0365 Å2
L1.2702 °2-0.1423 °2-0.1892 °2-1.25 °20.4624 °2--3.1739 °2
S-0.1195 Å °0.0264 Å °0.0613 Å °-0.0751 Å °0.0652 Å °0.0339 Å °-0.092 Å °-0.0387 Å °0.0543 Å °
Refinement TLS groupSelection details: { A|* }

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