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

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Basic information

Entry
Database: PDB / ID: 3qcq
TitlePhosphoinositide-Dependent Kinase-1 (PDK1) kinase domain with 6-(3-Amino-1H-indazol-6-yl)-N4-ethyl-2,4-pyrimidinediamine
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein-ligand complex / Kinase / Signal transduction / ATP binding Phosphoinositide binding for full length / Phoshorylation on S241 / celluar and membrane associated / 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 / 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 / GPVI-mediated activation cascade / cellular response to epidermal growth factor stimulus / 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 / 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 / Regulation of TP53 Degradation / cell migration / Downstream TCR signaling / PIP3 activates AKT signaling / insulin receptor signaling pathway / 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 / 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-3Q0 / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.501 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

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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)36,5799
Polymers35,6531
Non-polymers9268
Water32418
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)123.718, 123.718, 47.062
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: 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.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-3Q0 / 6-(3-amino-2H-indazol-6-yl)-N~4~-ethylpyrimidine-2,4-diamine


Mass: 269.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H15N7
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 2.92 Å3/Da / Density % sol: 57.82 %
Crystal growTemperature: 323 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 1.9-2 M ammonium sulfate and 0.1 M tris pH 9 plus 15 - 30 % glycerol for freezing, VAPOR DIFFUSION, SITTING DROP, temperature 323K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 1, 2008
RadiationMonochromator: diamond / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. all: 14544 / Num. obs: 14515 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 10.7 % / Rmerge(I) obs: 0.123 / Χ2: 1.007 / Net I/σ(I): 10.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.5-2.598.50.47114220.973100
2.59-2.6910.20.40814071.06199.4
2.69-2.8210.80.28714700.99399.6
2.82-2.96110.23214200.97699.8
2.96-3.1511.10.18514470.98599.8
3.15-3.3911.20.14914391.01299.9
3.39-3.7311.30.1214431.02299.9
3.73-4.2711.10.09614730.994100
4.27-5.3811.10.08414650.97899.9
5.38-5010.60.05515291.07399.7

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACT3.1data extraction
MAR345dtbdata collection
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.501→43.089 Å / Occupancy max: 1 / Occupancy min: 0.12 / SU ML: 0.34 / σ(F): 0.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2512 1416 10.09 %random
Rwork0.1738 ---
all0.1815 14544 --
obs0.1815 14029 96.51 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 35.875 Å2 / ksol: 0.369 e/Å3
Displacement parametersBiso max: 175.82 Å2 / Biso mean: 41.0497 Å2 / Biso min: 3.88 Å2
Baniso -1Baniso -2Baniso -3
1-0.579 Å20 Å20 Å2
2--0.579 Å20 Å2
3----1.1579 Å2
Refinement stepCycle: LAST / Resolution: 2.501→43.089 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2243 0 59 18 2320
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082384
X-RAY DIFFRACTIONf_angle_d1.1343204
X-RAY DIFFRACTIONf_chiral_restr0.071344
X-RAY DIFFRACTIONf_plane_restr0.005403
X-RAY DIFFRACTIONf_dihedral_angle_d16.408867
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5015-2.59090.34161250.2271136126189
2.5909-2.69460.3241320.19971162129491
2.6946-2.81720.25851340.16771265139995
2.8172-2.96570.28491420.17081230137296
2.9657-3.15140.30981410.18951270141197
3.1514-3.39470.27931480.18891276142499
3.3947-3.73610.25971420.16661280142299
3.7361-4.27630.18981470.138313231470100
4.2763-5.38610.18181430.141413181461100
5.3861-43.09490.25181620.18781353151599

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