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- PDB-2xch: Crystal structure of PDK1 in complex with a pyrazoloquinazoline i... -

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Basic information

Entry
Database: PDB / ID: 2xch
TitleCrystal structure of PDK1 in complex with a pyrazoloquinazoline inhibitor
Components3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1
KeywordsTRANSFERASE / PI3-KINASE SIGNALLING / SERINE/THREONINE-PROTEIN KINASE / ATP-BINDING
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-CKG / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsAngiolini, M. / Banfi, P. / Casale, E. / Casuscelli, F. / Fiorelli, C. / Saccardo, M.B. / Silvagni, M. / Zuccotto, F.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Structure-Based Optimization of Potent Pdk1 Inhibitors.
Authors: Angiolini, M. / Banfi, P. / Casale, E. / Casuscelli, F. / Fiorelli, C. / Saccardo, M.B. / Silvagni, M. / Zuccotto, F.
History
DepositionApr 23, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 28, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _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)36,96014
Polymers35,4281
Non-polymers1,53213
Water2,702150
1
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)73,92028
Polymers70,8552
Non-polymers3,06526
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555x-y,-y,-z+1/31
Buried area7690 Å2
ΔGint-211.9 kcal/mol
Surface area24410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)122.886, 122.886, 47.249
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: 35427.609 Da / Num. of mol.: 1 / Fragment: KINASE CATALYTIC DOMAIN, RESIDUES 1-309
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O15530, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-CKG / 8-(CYCLOHEXA-2,5-DIEN-1-YLIDENEAMINO)-1-(PIPERIDIN-4-YLMETHYL)-4,5-DIHYDRO-1H-PYRAZOLO[4,3-H]QUINAZOLINE-3-CARBOXAMIDE


Mass: 403.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25N7O
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 150 / 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: 2.9 Å3/Da / Density % sol: 57.3 % / Description: NONE
Crystal growDetails: 2.0 M AMMONIUM SULFATE,0.1 M TRIS PH8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.979
DetectorType: ADSC CCD / Detector: CCD / Date: Nov 27, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. obs: 27886 / % possible obs: 99.7 % / Observed criterion σ(I): 0 / Redundancy: 4.5 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 9.8
Reflection shellResolution: 2→2.1 Å / Redundancy: 4 % / Rmerge(I) obs: 0.39 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1H1W

1h1w


Resolution: 2→30 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.933 / SU B: 3.104 / SU ML: 0.09 / Cross valid method: THROUGHOUT / ESU R: 0.151 / ESU R Free: 0.142 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22567 1398 5 %RANDOM
Rwork0.18878 ---
obs0.19061 26472 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.771 Å2
Baniso -1Baniso -2Baniso -3
1-1.05 Å20.53 Å20 Å2
2--1.05 Å20 Å2
3----1.58 Å2
Refinement stepCycle: LAST / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2285 0 96 150 2531
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222428
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4682.0163271
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7385277
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.45423.67109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.22215.035430
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.1341514
X-RAY DIFFRACTIONr_chiral_restr0.1010.2343
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021778
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2060.21116
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3140.21627
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1690.2160
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.50.263
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.220.220
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.1541.51441
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.8722254
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.67231122
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.0444.51017
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: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.282 100 -
Rwork0.217 1962 -
obs--99.71 %

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