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- PDB-3qcs: Phosphoinositide-Dependent Kinase-1 (PDK1) kinase domain with 6-[... -

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Basic information

Entry
Database: PDB / ID: 3qcs
TitlePhosphoinositide-Dependent Kinase-1 (PDK1) kinase domain with 6-[2-Amino-6-(4-morpholinyl)-4-pyrimidinyl]-1H-indazol-3-amine
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / AGC kinase / signal transduction / ATP & Phosphoinositide / Phosphorylation on S241 / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / hyperosmotic response / RSK activation / regulation of canonical NF-kappaB signal transduction / positive regulation of vascular endothelial cell proliferation ...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 / hyperosmotic response / RSK activation / 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 / phospholipase binding / positive regulation of blood vessel endothelial cell migration / Role of LAT2/NTAL/LAB on calcium mobilization / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Estrogen-stimulated signaling through PRKCZ / negative regulation of endothelial cell apoptotic process / 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 / cellular response to epidermal growth factor stimulus / activation of protein kinase B activity / Integrin signaling / insulin-like growth factor receptor signaling pathway / positive regulation of release of sequestered calcium ion into cytosol / VEGFR2 mediated vascular permeability / VEGFR2 mediated cell proliferation / cell projection / peptidyl-threonine phosphorylation / positive regulation of protein localization to plasma membrane / calcium-mediated signaling / negative regulation of transforming growth factor beta receptor signaling pathway / negative regulation of protein kinase activity / epidermal growth factor receptor signaling pathway / CLEC7A (Dectin-1) signaling / cellular response to insulin stimulus / FCERI mediated NF-kB activation / positive regulation of angiogenesis / G beta:gamma signalling through PI3Kgamma / Regulation of TP53 Degradation / cell migration / Downstream TCR signaling / PIP3 activates AKT signaling / insulin receptor signaling pathway / actin cytoskeleton organization / cytoplasmic vesicle / protein autophosphorylation / postsynaptic density / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site ...PDK1-type, PH domain / PH domain / PDPK1 family / : / 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-3Q1 / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.487 Å
AuthorsMedina, J.R. / Becker, C.J. / Blackledge, C.W. / Duquenne, C. / Feng, Y. / Grant, S.W. / Heerding, D. / Li, W.H. / Miller, W.H. / Romeril, S.P. ...Medina, J.R. / Becker, C.J. / Blackledge, C.W. / Duquenne, C. / Feng, Y. / Grant, S.W. / Heerding, D. / Li, W.H. / Miller, W.H. / Romeril, S.P. / Scherzer, D. / Shu, A. / Bobko, M.A. / Chadderton, A.R. / Dumble, M. / Gradiner, C.M. / Gilbert, S. / Liu, Q. / Rabindran, S.K. / Sudakin, V. / Xiang, H. / Brady, P.G. / Campobasso, N. / Ward, P. / Axten, J.M.
Citation
Journal: J.Med.Chem. / Year: 2011
Title: Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors.
Authors: Medina, J.R. / Becker, C.J. / Blackledge, C.W. / Duquenne, C. / Feng, Y. / Grant, S.W. / Heerding, D. / Li, W.H. / Miller, W.H. / Romeril, S.P. / Scherzer, D. / Shu, A. / Bobko, M.A. / ...Authors: Medina, J.R. / Becker, C.J. / Blackledge, C.W. / Duquenne, C. / Feng, Y. / Grant, S.W. / Heerding, D. / Li, W.H. / Miller, W.H. / Romeril, S.P. / Scherzer, D. / Shu, A. / Bobko, M.A. / Chadderton, A.R. / Dumble, M. / Gardiner, C.M. / Gilbert, S. / Liu, Q. / Rabindran, S.K. / Sudakin, V. / Xiang, H. / Brady, P.G. / Campobasso, N. / Ward, P. / Axten, J.M.
#1: Journal: ACS Med. Chem. Lett. / Year: 2010
Title: Aminoindazole PDK1 Inhibitors: A Case Study in Fragment-Based Drug Discovery
Authors: Medina, J.R. / Blackledge, C.W. / Heerding, D.A. / Campobasso, N. / Ward, P. / Briand, J. / Wright, L. / Axten, J.M.
History
DepositionJan 17, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software
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_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_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)36,81311
Polymers35,6531
Non-polymers1,16010
Water36020
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)123.848, 123.848, 47.034
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-3-

SO4

Detailsbiological unit is the same as asym.

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Components

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


Mass: 35652.852 Da / Num. of mol.: 1 / Fragment: kinase domain, residues 73-358
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDPK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O15530, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-3Q1 / 6-[2-amino-6-(morpholin-4-yl)pyrimidin-4-yl]-2H-indazol-3-amine


Mass: 311.342 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H17N7O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 2.92 Å3/Da / Density % sol: 57.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 1.9-2 M ammonium sulfate,0.1 M tris pH 9. and 5mM ATP 15-30% glycerol plus mother liquor mixed with inhibitor served as the cryo-protectant before being frozen in liquid nitrogen, VAPOR ...Details: 1.9-2 M ammonium sulfate,0.1 M tris pH 9. and 5mM ATP 15-30% glycerol plus mother liquor mixed with inhibitor served as the cryo-protectant before being frozen in liquid nitrogen, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 1, 2008
RadiationMonochromator: diamond / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.487→50 Å / Num. all: 14803 / Num. obs: 14774 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 10.2 % / Rmerge(I) obs: 0.091 / Χ2: 0.938 / Net I/σ(I): 12.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.487-2.596.90.48414390.7598.8
2.59-2.6990.38414620.77799.7
2.69-2.82100.28514510.846100
2.82-2.9610.40.20514870.937100
2.96-3.1510.60.15914640.976100
3.15-3.3910.90.1214700.988100
3.39-3.7311.20.08614650.999100
3.73-4.2711.20.07114890.97100
4.27-5.3811.10.07214970.976100
5.38-5010.60.05215501.03799.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACT3.1data extraction
MAR345dtbdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.487→40.539 Å / Occupancy max: 1 / Occupancy min: 0.07 / SU ML: 0.36 / σ(F): 0.14 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2511 1435 10.06 %RANDOM
Rwork0.1744 ---
all0.1822 14823 --
obs0.1822 14265 96.23 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 38.954 Å2 / ksol: 0.37 e/Å3
Displacement parametersBiso max: 184.61 Å2 / Biso mean: 43.9876 Å2 / Biso min: 5.56 Å2
Baniso -1Baniso -2Baniso -3
1--2.4457 Å2-0 Å20 Å2
2---2.4457 Å20 Å2
3---4.8914 Å2
Refinement stepCycle: LAST / Resolution: 2.487→40.539 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2243 0 72 20 2335
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052388
X-RAY DIFFRACTIONf_angle_d0.9633210
X-RAY DIFFRACTIONf_chiral_restr0.063344
X-RAY DIFFRACTIONf_plane_restr0.003403
X-RAY DIFFRACTIONf_dihedral_angle_d15.904866
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4871-2.57590.33621260.23271154128088
2.5759-2.67910.33021380.20961225136392
2.6791-2.8010.2921410.19391220136193
2.801-2.94860.25071430.17911277142096
2.9486-3.13330.26081440.17681261140596
3.1333-3.37510.28681500.17571310146099
3.3751-3.71450.22561400.16231310145099
3.7145-4.25150.20891450.13261337148299
4.2515-5.35450.20921510.139613491500100
5.3545-40.54410.23391570.191913871544100

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