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- PDB-2pe0: CRYSTAL STRUCTURE OF HUMAN PHOSPHOINOSITIDE-DEPENDENT PROTEIN KIN... -

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Entry
Database: PDB / ID: 2pe0
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1 (PDK1) 5-Hydroxy-3-[1-(1H-pyrrol-2-yl)-eth-(Z)-ylidene]-1,3-dihydro-indol-2-one COMPLEX
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE / PROTEIN INHIBITOR COMPLEX / SERINE KINASE
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-39Z / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / DIFFERENCE FOURIER PLUS REFINEMENT / Resolution: 2.35 Å
AuthorsWhitlow, M. / Adler, M.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: Design, synthesis and biological activity.
Authors: Islam, I. / Bryant, J. / Chou, Y.L. / Kochanny, M.J. / Lee, W. / Phillips, G.B. / Yu, H. / Adler, M. / Whitlow, M. / Ho, E. / Lentz, D. / Polokoff, M.A. / Subramanyam, B. / Wu, J.M. / Zhu, D. ...Authors: Islam, I. / Bryant, J. / Chou, Y.L. / Kochanny, M.J. / Lee, W. / Phillips, G.B. / Yu, H. / Adler, M. / Whitlow, M. / Ho, E. / Lentz, D. / Polokoff, M.A. / Subramanyam, B. / Wu, J.M. / Zhu, D. / Feldman, R.I. / Arnaiz, D.O.
#1: Journal: To be Published / Year: 2007
Title: Indolinone based Phhosphoinositide-Dependent Kinase-1 (PDK1) inhibitors- Part 2: Optimization of BX-517
Authors: Islam, I. / Brown, G. / Bryant, J. / Hrvatin, P. / Kochanny, M.J. / Phillips, G.B. / Yuan, S. / Adler, M. / Whitlow, M. / Lentz, D. / Polokoff, M.A. / Wu, J. / Shen, J. / Walters, J. / Ho, E. ...Authors: Islam, I. / Brown, G. / Bryant, J. / Hrvatin, P. / Kochanny, M.J. / Phillips, G.B. / Yuan, S. / Adler, M. / Whitlow, M. / Lentz, D. / Polokoff, M.A. / Wu, J. / Shen, J. / Walters, J. / Ho, E. / Subramanyam, B. / Zhu, D. / Feldman, R.I. / Arnaiz, D.O.
#2: Journal: J.Biol.Chem. / Year: 2005
Title: Novel Small Molecule Inhibitors of 3-Phosphoinositide-Dependent Kinase-1.
Authors: Feldman, R.I. / Wu, J.M. / Polokoff, M.A. / Kochanny, M.J. / Dinter, H. / Zhu, D. / Biroc, S.L. / Alicke, B. / Bryant, J. / Yuan, S. / Buckman, B.O. / Lentz, D. / Ferrer, M. / Whitlow, M. / ...Authors: Feldman, R.I. / Wu, J.M. / Polokoff, M.A. / Kochanny, M.J. / Dinter, H. / Zhu, D. / Biroc, S.L. / Alicke, B. / Bryant, J. / Yuan, S. / Buckman, B.O. / Lentz, D. / Ferrer, M. / Whitlow, M. / Adler, M. / Finster, S. / Chang, Z. / Arnaiz, D.O.
#3: Journal: Embo J. / Year: 2002
Title: High Resolution Crystal Structure of the Human Pdk1 Catalytic Domain Defines the Regulatory Phosphopeptide Docking Site.
Authors: Biondi, R.M. / Komander, D. / Thomas, C.C. / Lizcano, J.M. / Deak, M. / Alessi, D.R. / Van Aalten, D.M.F.
History
DepositionApr 1, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)33,8397
Polymers33,1301
Non-polymers7096
Water88349
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)123.951, 123.951, 47.217
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11A-797-

HOH

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Components

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


Mass: 33130.117 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDPK1, PDK1 / Plasmid: PDK1-CAT/PBB4.5 / Production host: unidentified baculovirus / Strain (production host): SF-21 CELLS
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-39Z / 5-HYDROXY-3-[(1R)-1-(1H-PYRROL-2-YL)ETHYL]-2H-INDOL-2-ONE


Mass: 240.257 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H12N2O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / 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: 3.2 Å3/Da / Density % sol: 62 %
Crystal growTemperature: 298 K / pH: 7.5
Details: AMMONIUM SULFATE, TRIS, EDTA, VAPOR DIFFUSION, HANGING DROP, temperature 298K, pH 7.50

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Data collection

DiffractionMean temperature: 96.2 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1.15
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 22, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.15 Å / Relative weight: 1
ReflectionResolution: 2.35→20 Å / Num. obs: 17172 / % possible obs: 97.4 % / Observed criterion σ(I): -3 / Redundancy: 2.62 % / Biso Wilson estimate: 23.4 Å2 / Rsym value: 0.1044 / Net I/σ(I): 7.44
Reflection shellResolution: 2.35→2.49 Å / Redundancy: 2.7 % / Mean I/σ(I) obs: 1.61 / Rsym value: 0.3974 / % possible all: 99

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Processing

Software
NameClassification
CNXrefinement
XTALVIEWrefinement
X-GENdata reduction
X-GENdata scaling
CNXphasing
RefinementMethod to determine structure: DIFFERENCE FOURIER PLUS REFINEMENT
Resolution: 2.35→19.71 Å / Rfactor Rfree error: 0.01 / Data cutoff high absF: 170420.85 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.24 613 4.1 %RANDOM
Rwork0.2 ---
obs0.202 14788 83.9 %-
all-17151 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 38.97 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso mean: 25.9 Å2
Baniso -1Baniso -2Baniso -3
1--0.64 Å28.68 Å20 Å2
2---0.64 Å20 Å2
3---1.28 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.32 Å0.26 Å
Luzzati d res low-5 Å
Luzzati sigma a0.3 Å0.26 Å
Refinement stepCycle: LAST / Resolution: 2.35→19.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2255 0 46 49 2350
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d21.4
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.62
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.862
X-RAY DIFFRACTIONc_mcangle_it2.92.5
X-RAY DIFFRACTIONc_scbond_it3.082.5
X-RAY DIFFRACTIONc_scangle_it4.483.5
LS refinement shellResolution: 2.35→2.5 Å / Rfactor Rfree error: 0.031 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2724 76 3.6 %
Rwork0.244 2018 -
obs--71.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
X-RAY DIFFRACTION4SPH.PARSPH.TOP
X-RAY DIFFRACTION5394.PAR394.TOP

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