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- PDB-1uu3: Structure of human PDK1 kinase domain in complex with LY333531 -

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Basic information

Entry
Database: PDB / ID: 1uu3
TitleStructure of human PDK1 kinase domain in complex with LY333531
Components3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE-1
KeywordsTRANSFERASE / PROTEIN KINASE / PKB / PDK1 / INHIBITOR / LY333531 / DIABETES / CANCER / SERINE/THREONINE-PROTEIN 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-LY4 / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsKomander, D. / Kular, G.S. / Schuttelkopf, A.W. / Deak, M. / Prakash, K.R. / Bain, J. / Elliot, M. / Garrido-Franco, M. / Kozikowski, A.P. / Alessi, D.R. / Van Aalten, D.M.F.
CitationJournal: Structure / Year: 2004
Title: Interactions of Ly333531 and Other Bisindolyl Maleimide Inhibitors with Pdk1
Authors: Komander, D. / Kular, G.S. / Schuttelkopf, A.W. / Deak, M. / Prakash, K.R. / Bain, J. / Elliot, M. / Garrido-Franco, M. / Kozikowski, A.P. / Alessi, D.R. / Van Aalten, D.M.F.
History
DepositionDec 15, 2003Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 4, 2004Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Apr 24, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc ...entity_src_gen / pdbx_database_proc / pdbx_database_status / pdbx_seq_map_depositor_info / struct_conn
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval ..._entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval / _pdbx_seq_map_depositor_info.one_letter_code_mod / _struct_conn.pdbx_leaving_atom_flag
Revision 1.4Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_database_status / pdbx_entity_nonpoly / pdbx_initial_refinement_model
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name
Revision 1.5Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)37,37617
Polymers35,4991
Non-polymers1,87816
Water5,080282
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)121.623, 121.623, 47.875
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-2090-

HOH

21A-2212-

HOH

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Components

#1: Protein 3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE-1 / HPDK1


Mass: 35498.688 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 51-360
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Description: BACULOVIRUS INFECTED / Plasmid: PFASTBAC1 / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: O15530, EC: 2.7.1.37
#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-LY4 / (9R)-9-[(DIMETHYLAMINO)METHYL]-6,7,10,11-TETRAHYDRO-9H,18H-5,21:12,17-DIMETHENODIBENZO[E,K]PYRROLO[3,4-H][1,4,13]OXADIA ZACYCLOHEXADECINE-18,20-DIONE / LY333531


Mass: 468.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H28N4O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 282 / 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 Å3/Da / Density % sol: 58 %
Crystal growpH: 7.5 / Details: 2.1 M AMMONIUM SULPHATE 0.1 M TRIS-HCL PH 7.2
Crystal grow
*PLUS
Method: vapor diffusion, sitting drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
10.5 mg/mlPDK11reservoir
210 mMDMSO1reservoir
37.3 mg/ml1drop

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 15, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 1.7→25 Å / Num. obs: 44644 / % possible obs: 99.9 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.044 / Net I/σ(I): 22.1
Reflection shellResolution: 1.7→1.76 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.278 / Mean I/σ(I) obs: 4.7 / % possible all: 98.6
Reflection
*PLUS
Highest resolution: 1.7 Å / Lowest resolution: 25 Å / Redundancy: 4.9 % / Num. measured all: 218856 / Rmerge(I) obs: 0.044
Reflection shell
*PLUS
% possible obs: 98.6 % / Redundancy: 3.7 % / Num. unique obs: 4344 / Num. measured obs: 15901 / Rmerge(I) obs: 0.278 / Mean I/σ(I) obs: 4.7

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1H1W

1h1w


Resolution: 1.7→25 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.937 / SU B: 1.428 / SU ML: 0.049 / Cross valid method: THROUGHOUT / ESU R: 0.087 / ESU R Free: 0.088 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS SOME SIDECHAINS REFINED WITH OCCUPANCY = 0.00 DUE TO DISORDER. SOME RESIDUES MUTATED TO ALANINE DUE TO DISORDER.
RfactorNum. reflection% reflectionSelection details
Rfree0.202 661 1.5 %RANDOM
Rwork0.173 ---
obs0.174 42657 96.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 17.71 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20.28 Å20 Å2
2--0.57 Å20 Å2
3----0.85 Å2
Refinement stepCycle: LAST / Resolution: 1.7→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2249 0 118 282 2649
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0222456
X-RAY DIFFRACTIONr_bond_other_d0.0020.022166
X-RAY DIFFRACTIONr_angle_refined_deg1.652.0133314
X-RAY DIFFRACTIONr_angle_other_deg0.87735064
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9435275
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.1160.2362
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.022559
X-RAY DIFFRACTIONr_gen_planes_other0.0150.02489
X-RAY DIFFRACTIONr_nbd_refined0.220.2481
X-RAY DIFFRACTIONr_nbd_other0.2440.22674
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0810.21377
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2171
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2230.215
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2570.271
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1550.223
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0351.51393
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.82622266
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.65331063
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.2254.51048
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.75 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.219 50
Rwork0.194 3075
Refinement
*PLUS
Lowest resolution: 25 Å / Rfactor Rfree: 0.204 / Rfactor Rwork: 0.176
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_d0.011
X-RAY DIFFRACTIONr_angle_d
X-RAY DIFFRACTIONr_angle_deg1.45

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