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- PDB-3rwp: Discovery of a Novel, Potent and Selective Inhibitor of 3-Phospho... -

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Basic information

Entry
Database: PDB / ID: 3rwp
TitleDiscovery of a Novel, Potent and Selective Inhibitor of 3-Phosphoinositide Dependent Kinase (PDK1)
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase domain / Transferase / Phosphoserine: SEP / 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-ABQ / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.92 Å
AuthorsGreasley, S.E. / Hickey, M. / Ferre, R.-A. / Krauss, M. / Cronin, C.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1).
Authors: Murphy, S.T. / Alton, G. / Bailey, S. / Baxi, S.M. / Burke, B.J. / Chappie, T.A. / Ermolieff, J. / Ferre, R. / Greasley, S. / Hickey, M. / Humphrey, J. / Kablaoui, N. / Kath, J. / Kazmirski, ...Authors: Murphy, S.T. / Alton, G. / Bailey, S. / Baxi, S.M. / Burke, B.J. / Chappie, T.A. / Ermolieff, J. / Ferre, R. / Greasley, S. / Hickey, M. / Humphrey, J. / Kablaoui, N. / Kath, J. / Kazmirski, S. / Kraus, M. / Kupchinsky, S. / Li, J. / Lingardo, L. / Marx, M.A. / Richter, D. / Tanis, S.P. / Tran, K. / Vernier, W. / Xie, Z. / Yin, M.J. / Yu, X.H.
History
DepositionMay 9, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 16, 2011Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2011Group: Database references
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software

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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)37,01812
Polymers35,6121
Non-polymers1,40611
Water3,693205
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: 3-phosphoinositide-dependent protein kinase 1
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)74,03624
Polymers71,2242
Non-polymers2,81222
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_556y,x,-z+11
Buried area8610 Å2
ΔGint-224 kcal/mol
Surface area24240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)122.982, 122.982, 47.505
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: 35611.844 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-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.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-ABQ / [4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](6-{[(3S,4R)-4-(4-fluorophenyl)tetrahydrofuran-3-yl]amino}pyrazin-2-yl)methanone


Mass: 461.491 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24FN7O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 205 / 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: 2.91 Å3/Da / Density % sol: 57.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 2.2M Ammonium Sulfate, 10mM EDTA, 5-10% glycerol, 0.1M HEPES, pH 7.0., VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 21, 2009
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.92→50 Å / Num. all: 31671 / Num. obs: 31671 / % possible obs: 99.6 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.3 % / Rsym value: 0.077 / Net I/σ(I): 15
Reflection shellResolution: 1.92→1.98 Å / Redundancy: 3.2 % / Mean I/σ(I) obs: 2.1 / Rsym value: 0.52 / % possible all: 99.9

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Processing

Software
NameClassification
HKL-2000data collection
REFMACrefinement
ARPmodel building
WARPmodel building
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.92→50 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.942 / SU B: 2.637 / SU ML: 0.078 / Cross valid method: THROUGHOUT / ESU R Free: 0.122 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21289 1600 5.1 %RANDOM
Rwork0.17167 ---
all0.17376 30059 --
obs0.17376 30059 99.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.159 Å2
Baniso -1Baniso -2Baniso -3
1-0.6 Å20.3 Å20 Å2
2--0.6 Å20 Å2
3----0.9 Å2
Refinement stepCycle: LAST / Resolution: 1.92→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2269 0 88 205 2562
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0280.0222416
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.2262.0143263
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6045278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.7223.611108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.09515.035425
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6921514
X-RAY DIFFRACTIONr_chiral_restr0.1710.2342
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0211829
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_it1.5061.51393
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.57122255
X-RAY DIFFRACTIONr_scbond_it3.83331023
X-RAY DIFFRACTIONr_scangle_it5.994.51008
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.92→1.969 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.274 124 -
Rwork0.266 2202 -
obs--99.53 %

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