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- PDB-4xx9: Crystal structure of PDK1 in complex with ATP and the PIF-pocket ... -

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Basic information

Entry
Database: PDB / ID: 4xx9
TitleCrystal structure of PDK1 in complex with ATP and the PIF-pocket ligand RF4
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTransferase/transferase inhibitor / Protein Kinase / Allostery / Transferase-transferase inhibitor complex
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
ADENOSINE-5'-TRIPHOSPHATE / Chem-RF4 / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsRettenmaier, T.J. / Wells, J.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA136779 United States
CitationJournal: J.Med.Chem. / Year: 2015
Title: Small-Molecule Allosteric Modulators of the Protein Kinase PDK1 from Structure-Based Docking.
Authors: Rettenmaier, T.J. / Fan, H. / Karpiak, J. / Doak, A. / Sali, A. / Shoichet, B.K. / Wells, J.A.
History
DepositionJan 29, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2015Group: Database references
Revision 1.2Sep 6, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Database references / Category: pdbx_audit_support / struct_ref_seq_dif
Item: _pdbx_audit_support.funding_organization / _struct_ref_seq_dif.details
Revision 1.4Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)36,8327
Polymers35,3361
Non-polymers1,4966
Water4,846269
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)148.626, 44.429, 47.639
Angle α, β, γ (deg.)90.000, 101.110, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 35335.512 Da / Num. of mol.: 1 / Fragment: UNP residues 50-359 / Mutation: Y288G, Q292A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDPK1, PDK1 / Plasmid: pFastBac HTB / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: O15530, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-RF4 / (2-{[2-(2,6-dimethylphenoxy)ethyl]sulfanyl}-1H-benzimidazol-1-yl)acetic acid


Mass: 356.439 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20N2O3S
#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.: 269 / 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: 2.18 Å3/Da / Density % sol: 43.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Precipitant: 0.1M HEPES, pH 7.5, 1.2M Na Citrate. Protein (21 mg/mL): 25mM Tris, pH 7.5, 0.5M NaCl, 1mM DTT, 15mM EDTA, 15mM ATP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.1159 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 18, 2013
RadiationMonochromator: Double flat crystal, Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1159 Å / Relative weight: 1
ReflectionResolution: 1.4→50 Å / Num. obs: 59563 / % possible obs: 99.7 % / Redundancy: 3.8 % / Biso Wilson estimate: 13.63 Å2 / Rmerge(I) obs: 0.065 / Χ2: 1.112 / Net I/av σ(I): 18.919 / Net I/σ(I): 13.6 / Num. measured all: 225159
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.4-1.453.60.82858751.11799.6
1.45-1.513.80.59959451.13699.9
1.51-1.583.80.42159501.15999.9
1.58-1.663.80.30159171.13999.9
1.66-1.763.90.20259511.16399.9
1.76-1.93.90.13559501.10499.8
1.9-2.093.90.08359351.00899.7
2.09-2.393.80.06559581.08299.7
2.39-3.023.70.05559761.10899.6
3.02-503.70.02961061.10199.3

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHENIX(phenix.refine: 1.9_1692)refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
HKL-2000data scaling
Coot8model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4AW1

4aw1


Resolution: 1.4→46.746 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 15.68 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1651 3010 5.05 %
Rwork0.1286 56551 -
obs0.1304 59561 99.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 80.5 Å2 / Biso mean: 22.2821 Å2 / Biso min: 6.12 Å2
Refinement stepCycle: final / Resolution: 1.4→46.746 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2348 0 124 276 2748
Biso mean--32.31 33.76 -
Num. residues----289
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0122573
X-RAY DIFFRACTIONf_angle_d1.4683498
X-RAY DIFFRACTIONf_chiral_restr0.088375
X-RAY DIFFRACTIONf_plane_restr0.008434
X-RAY DIFFRACTIONf_dihedral_angle_d14.975996
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 22

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.4-1.42560.27251400.2232417255795
1.4256-1.44890.28471230.201525732696100
1.4489-1.47390.2421310.178425462677100
1.4739-1.50070.20571310.158725682699100
1.5007-1.52960.20231300.157925932723100
1.5296-1.56080.21051240.14225612685100
1.5608-1.59470.19131370.132525842721100
1.5947-1.63180.18011530.129925492702100
1.6318-1.67270.19541400.120325512691100
1.6727-1.71790.16651410.112425872728100
1.7179-1.76840.16511410.107225802721100
1.7684-1.82550.14651340.103225352669100
1.8255-1.89080.1491460.100625732719100
1.8908-1.96650.14091370.09825742711100
1.9665-2.0560.13461400.09625672707100
2.056-2.16440.13961400.101525752715100
2.1644-2.30.13591480.105925492697100
2.3-2.47750.15671400.11425962736100
2.4775-2.72680.18081190.1325992718100
2.7268-3.12130.17341360.136125982734100
3.1213-3.93230.17191350.129726172752100
3.9323-46.77230.1511440.15562659280399

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