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- PDB-3qcx: Phosphoinositide-Dependent Kinase-1 (PDK1) kinase domain with 6-{... -

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Basic information

Entry
Database: PDB / ID: 3qcx
TitlePhosphoinositide-Dependent Kinase-1 (PDK1) kinase domain with 6-{2-Amino-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1H-indazol-3-amine
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase domain / AGC kinase / Signal transduction / Phosphorylation on s241 / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / negative regulation of cardiac muscle cell apoptotic process ...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 / negative regulation of cardiac muscle cell apoptotic process / positive regulation of vascular endothelial cell proliferation / 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 / 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 / positive regulation of release of sequestered calcium ion into cytosol / insulin-like growth factor receptor signaling pathway / VEGFR2 mediated vascular permeability / VEGFR2 mediated cell proliferation / cell projection / calcium-mediated signaling / positive regulation of protein localization to plasma membrane / negative regulation of transforming growth factor beta receptor signaling pathway / peptidyl-threonine phosphorylation / 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 / cell migration / Regulation of TP53 Degradation / Downstream TCR signaling / PIP3 activates AKT signaling / insulin receptor signaling pathway / cytoplasmic vesicle / actin cytoskeleton organization / postsynaptic density / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation / focal adhesion / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
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-3Q2 / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsMedina, J.R. / Becker, C.J. / Blackledge, C.W. / Duquenne, C. / Feng, Y. / Grant, S.W. / Heerding, D. / Li, W.H. / Miller, W.H. / Romeril, S.P. ...Medina, J.R. / Becker, C.J. / Blackledge, C.W. / Duquenne, C. / Feng, Y. / Grant, S.W. / Heerding, D. / Li, W.H. / Miller, W.H. / Romeril, S.P. / Scherzer, D. / Shu, A. / Bobko, M.A. / Chadderton, A.R. / Dumble, M. / Gradiner, C.M. / Gilbert, S. / Liu, Q. / Rabindran, S.K. / Sudakin, V. / Xiang, H. / Brady, P.G. / Campobasso, N. / Ward, P. / Axten, J.M.
Citation
Journal: J.Med.Chem. / Year: 2011
Title: Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors.
Authors: Medina, J.R. / Becker, C.J. / Blackledge, C.W. / Duquenne, C. / Feng, Y. / Grant, S.W. / Heerding, D. / Li, W.H. / Miller, W.H. / Romeril, S.P. / Scherzer, D. / Shu, A. / Bobko, M.A. / ...Authors: Medina, J.R. / Becker, C.J. / Blackledge, C.W. / Duquenne, C. / Feng, Y. / Grant, S.W. / Heerding, D. / Li, W.H. / Miller, W.H. / Romeril, S.P. / Scherzer, D. / Shu, A. / Bobko, M.A. / Chadderton, A.R. / Dumble, M. / Gardiner, C.M. / Gilbert, S. / Liu, Q. / Rabindran, S.K. / Sudakin, V. / Xiang, H. / Brady, P.G. / Campobasso, N. / Ward, P. / Axten, J.M.
#1: Journal: ACS Med. Chem. Lett. / Year: 2010
Title: Aminoindazole PDK1 Inhibitors: A Case Study in Fragment-Based Drug Discovery
Authors: Medina, J.R. / Blackledge, C.W. / Heerding, D.A. / Campobasso, N. / Ward, P. / Briand, J. / Wright, L. / Axten, J.M.
History
DepositionJan 17, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 16, 2011Group: Atomic model

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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)37,01513
Polymers35,6531
Non-polymers1,36212
Water88349
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)123.352, 123.352, 46.963
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-397-

HOH

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Components

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


Mass: 35652.852 Da / Num. of mol.: 1 / Fragment: kinase domain, residues 48-359
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDK1, PDPK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O15530, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-3Q2 / 6-{2-amino-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}-2H-indazol-3-amine


Mass: 325.368 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H19N7O
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 49 / 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: 2.89 Å3/Da / Density % sol: 57.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 1.9-2 M ammonium sulfate,0.1 M tris pH 9. and 5mM ATP; 15-30% glycerol plus mother liquor mixed with inhibitor served as the cryo-protectant before being frozen in liquid nitrogen, Vapor ...Details: 1.9-2 M ammonium sulfate,0.1 M tris pH 9. and 5mM ATP; 15-30% glycerol plus mother liquor mixed with inhibitor served as the cryo-protectant before being frozen in liquid nitrogen, Vapor diffusion. sitting drop, temperature 293K

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Data collection

DiffractionMean temperature: 160 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.1271 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Dec 11, 2008 / Details: diamond
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1271 Å / Relative weight: 1
ReflectionResolution: 2.3→30 Å / Num. all: 18547 / Num. obs: 18547 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 4.9 % / Rmerge(I) obs: 0.077 / Χ2: 1.071 / Net I/σ(I): 12
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.3-2.384.30.53718391.00999.7
2.38-2.484.60.43618391.068100
2.48-2.594.80.35718371.078100
2.59-2.734.80.2718261.083100
2.73-2.94.90.18718311.099100
2.9-3.1250.13518611.088100
3.12-3.435.20.08718401.081100
3.43-3.935.20.06618601.08599.9
3.93-4.955.20.05118701.046100
4.95-3050.03719441.06399.9

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACT3.1data extraction
MAR345dtbdata collection
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→28.374 Å / Occupancy max: 1 / Occupancy min: 0.34 / SU ML: 0.31 / σ(F): 0.05 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2252 1746 9.91 %
Rwork0.1795 --
obs0.1841 17623 95.04 %
all-18543 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 58.834 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso max: 95.9 Å2 / Biso mean: 41.9516 Å2 / Biso min: 24.87 Å2
Baniso -1Baniso -2Baniso -3
1--3.4179 Å2-0 Å20 Å2
2---3.4179 Å20 Å2
3---6.8358 Å2
Refinement stepCycle: LAST / Resolution: 2.3→28.374 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2238 0 84 49 2371
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012375
X-RAY DIFFRACTIONf_angle_d1.3533207
X-RAY DIFFRACTIONf_chiral_restr0.089344
X-RAY DIFFRACTIONf_plane_restr0.005400
X-RAY DIFFRACTIONf_dihedral_angle_d18.231856
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3-2.36620.29481340.20981226136087
2.3662-2.44260.2131320.1851209134189
2.4426-2.52980.3051310.18841238136990
2.5298-2.63110.27441360.19891286142292
2.6311-2.75070.27291410.19961299144094
2.7507-2.89560.25581480.18251301144996
2.8956-3.07680.24461440.17521346149096
3.0768-3.3140.23481510.18131367151898
3.314-3.64690.21291550.16111366152198
3.6469-4.17320.20321580.15281383154199
4.1732-5.25240.1831520.159314091561100
5.2524-28.37660.21721640.208614471611100

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