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- PDB-2pe1: CRYSTAL STRUCTURE OF HUMAN PHOSPHOINOSITIDE-DEPENDENT PROTEIN KIN... -

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Basic information

Entry
Database: PDB / ID: 2pe1
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1 (PDK1) {2-Oxo-3-[1-(1H-pyrrol-2-yl)-eth-(Z)-ylidene]-2,3-dihydro-1H-indol-5-yl}-urea {BX-517} COMPLEX
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE / PROTEIN INHIBITOR COMPLEX / SERINE KINASE
Function / homology
Function and homology information


intracellular signaling cassette / 3-phosphoinositide-dependent protein kinase activity / Activation of AKT2 / regulation of mast cell degranulation / type B pancreatic cell development / negative regulation of toll-like receptor signaling pathway / RSK activation / hyperosmotic response / regulation of canonical NF-kappaB signal transduction / positive regulation of vascular endothelial cell proliferation ...intracellular signaling cassette / 3-phosphoinositide-dependent protein kinase activity / Activation of AKT2 / regulation of mast cell degranulation / type B pancreatic cell development / negative regulation of toll-like receptor signaling pathway / 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 / positive regulation of blood vessel endothelial cell migration / Role of LAT2/NTAL/LAB on calcium mobilization / negative regulation of endothelial cell apoptotic process / Estrogen-stimulated signaling through PRKCZ / vascular endothelial cell response to laminar fluid shear stress / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / phospholipase binding / GPVI-mediated activation cascade / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / T cell costimulation / extrinsic apoptotic signaling pathway / Integrin signaling / insulin-like growth factor receptor signaling pathway / cellular response to epidermal growth factor stimulus / 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 / calcium-mediated signaling / negative regulation of transforming growth factor beta receptor signaling pathway / CLEC7A (Dectin-1) signaling / FCERI mediated NF-kB activation / epidermal growth factor receptor signaling pathway / 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 / protein autophosphorylation / actin cytoskeleton organization / cytoplasmic vesicle / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / protein phosphorylation / non-specific serine/threonine protein kinase / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / postsynaptic density / intracellular signal transduction / 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-517 / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / DIFFERENCE FOURIER PLUS REFINEMENT / Resolution: 2.14 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 1.3Nov 6, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)33,9738
Polymers33,1301
Non-polymers8437
Water1,65792
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)125.234, 125.234, 47.696
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: 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-517 / 1-{2-OXO-3-[(1R)-1-(1H-PYRROL-2-YL)ETHYL]-2H-INDOL-5-YL}UREA


Mass: 282.297 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H14N4O2
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / 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: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 2, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.14→20 Å / Num. obs: 23847 / % possible obs: 99.5 % / Observed criterion σ(I): 4.5 / Redundancy: 3.36 % / Biso Wilson estimate: 8.1 Å2 / Rsym value: 0.115 / Net I/σ(I): 5.89
Reflection shellResolution: 2.14→2.27 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 1.7 / Rsym value: 0.3769 / % 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: 2.14→19.91 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 67445.14 / 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
Rfree0.282 903 3.9 %RANDOM
Rwork0.222 ---
obs0.224 23028 96 %-
all-23831 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 54.01 Å2 / ksol: 0.38 e/Å3
Displacement parametersBiso mean: 17.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å21.24 Å20 Å2
2---0.11 Å20 Å2
3---0.22 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.35 Å0.27 Å
Luzzati d res low-5 Å
Luzzati sigma a0.33 Å0.31 Å
Refinement stepCycle: LAST / Resolution: 2.14→19.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2255 0 55 92 2402
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
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.71
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.862
X-RAY DIFFRACTIONc_mcangle_it2.712.5
X-RAY DIFFRACTIONc_scbond_it2.82.5
X-RAY DIFFRACTIONc_scangle_it3.943.5
LS refinement shellResolution: 2.14→2.27 Å / Rfactor Rfree error: 0.025 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.3003 147 4.2 %
Rwork0.2767 3392 -
obs--89.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARWATER.TOP
X-RAY DIFFRACTION3ION.PARAMION.TOP
X-RAY DIFFRACTION4SPH.PARSPH.TOP
X-RAY DIFFRACTION5517.PAR517.TOP
X-RAY DIFFRACTION6SO4.PARSO4.TOP
X-RAY DIFFRACTION7GOL.PARGOL.TOP

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