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- PDB-2pe2: CRYSTAL STRUCTURE OF HUMAN PHOSPHOINOSITIDE-DEPENDENT PROTEIN KIN... -

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Entry
Database: PDB / ID: 2pe2
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1 (PDK1) 3-{5-[2-Oxo-5-ureido-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrol-3-yl}-N-(2-piperidin-1-yl-ethyl)-benzamide 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 / cytoplasm / cytosol
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-464 / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / DIFFERENCE FOURIER PLUS REFINEMENT / Resolution: 2.13 Å
AuthorsWhitlow, M. / Adler, M.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: Indolinone based phosphoinositide-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.
#1: Journal: To be Published / Year: 2007
Title: Indolinone based Phhosphoinositide-Dependent Kinase-1 (PDK1) inhibitors- Part 1: Design, Synthesis and Billogical 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, ...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.
#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 19, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Derived calculations / Version format compliance
Revision 1.3Nov 20, 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)34,65413
Polymers33,1301
Non-polymers1,52412
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
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)69,30726
Polymers66,2602
Non-polymers3,04724
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_556-x,-x+y,-z+5/31
Buried area8800 Å2
ΔGint-100 kcal/mol
Surface area24870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)123.223, 123.223, 47.386
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.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-464 / 3-[5-({5-[(AMINOCARBONYL)AMINO]-2-OXO-2H-INDOL-3-YL}METHYL)-1H-PYRROL-3-YL]-N-(2-PIPERIDIN-1-YLETHYL)BENZAMIDE


Mass: 498.576 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30N6O3
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 161 / 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 / Method: vapor diffusion, hanging drop / 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: Mar 30, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.13→50 Å / Num. obs: 22919 / % possible obs: 98.1 % / Observed criterion σ(I): -3 / Redundancy: 3.28 % / Biso Wilson estimate: 15 Å2 / Rsym value: 0.0665 / Net I/σ(I): 9.95
Reflection shellResolution: 2.13→2.26 Å / Redundancy: 3.16 % / Mean I/σ(I) obs: 1.72 / Rsym value: 0.3512 / % possible all: 97.4

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Processing

Software
NameClassification
CNXrefinement
XTALVIEWrefinement
X-GENdata reduction
X-GENdata scaling
X-PLORphasing
RefinementMethod to determine structure: DIFFERENCE FOURIER PLUS REFINEMENT
Resolution: 2.13→19.72 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 137258.17 / 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
Rfree0.215 843 4.2 %RANDOM
Rwork0.188 ---
obs0.189 20101 86 %-
all-22905 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 71.76 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso mean: 27.1 Å2
Baniso -1Baniso -2Baniso -3
1-0.24 Å22.96 Å20 Å2
2--0.24 Å20 Å2
3----0.47 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.31 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 2.13→19.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2255 0 100 161 2516
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
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_d20.5
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.64
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.371.5
X-RAY DIFFRACTIONc_mcangle_it2.142
X-RAY DIFFRACTIONc_scbond_it2.442
X-RAY DIFFRACTIONc_scangle_it3.663
LS refinement shellResolution: 2.13→2.26 Å / Rfactor Rfree error: 0.029 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.3023 107 4 %
Rwork0.2419 2581 -
obs--69.9 %
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 DIFFRACTION5464.PAR464.TOP

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