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- PDB-5mrd: Human PDK1-PKCiota Kinase Chimera in Complex with Allosteric Comp... -

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Basic information

Entry
Database: PDB / ID: 5mrd
TitleHuman PDK1-PKCiota Kinase Chimera in Complex with Allosteric Compound PS267 Bound to the PIF-Pocket
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE / Protein Kinase / Allosteric Regulation / Small Compounds / PIF-pocket
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 / CD28 dependent PI3K/Akt signaling / phospholipase binding / 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 / GPVI-mediated activation cascade / cellular response to epidermal growth factor stimulus / T cell costimulation / 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 / 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 / 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 / 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
ADENOSINE-5'-TRIPHOSPHATE / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / ethyl / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.41 Å
AuthorsArencibia, J.M. / Froehner, W. / Krupa, M. / Pastor-Flores, D. / Merker, P. / Oellerich, T. / Neimanis, S. / Schmithals, C. / Koeberle, V. / Suess, E. ...Arencibia, J.M. / Froehner, W. / Krupa, M. / Pastor-Flores, D. / Merker, P. / Oellerich, T. / Neimanis, S. / Schmithals, C. / Koeberle, V. / Suess, E. / Zeuzem, S. / Stark, H. / Piiper, A. / Odadzic, D. / Schulze, J.O. / Biondi, R.M.
Funding support Germany, 3items
OrganizationGrant numberCountry
German Research FoundationBI 1044/2-3 Germany
German Research FoundationBI 1044/4-1 Germany
German Research FoundationBI 1044/8-1 Germany
CitationJournal: ACS Chem. Biol. / Year: 2017
Title: An Allosteric Inhibitor Scaffold Targeting the PIF-Pocket of Atypical Protein Kinase C Isoforms.
Authors: Arencibia, J.M. / Frohner, W. / Krupa, M. / Pastor-Flores, D. / Merker, P. / Oellerich, T. / Neimanis, S. / Schmithals, C. / Koberle, V. / Su, E. / Zeuzem, S. / Stark, H. / Piiper, A. / ...Authors: Arencibia, J.M. / Frohner, W. / Krupa, M. / Pastor-Flores, D. / Merker, P. / Oellerich, T. / Neimanis, S. / Schmithals, C. / Koberle, V. / Su, E. / Zeuzem, S. / Stark, H. / Piiper, A. / Odadzic, D. / Schulze, J.O. / Biondi, R.M.
History
DepositionDec 22, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 18, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2017Group: Database references
Revision 1.2Mar 1, 2017Group: Database references
Revision 1.3Oct 16, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / reflns_shell / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jan 17, 2024Group: 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

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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)36,5206
Polymers35,2811
Non-polymers1,2395
Water5,927329
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1330 Å2
ΔGint-1 kcal/mol
Surface area13320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)149.110, 44.480, 47.810
Angle α, β, γ (deg.)90.00, 101.96, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 35281.379 Da / Num. of mol.: 1
Mutation: K76S, L113V, I118V, I119N, V124I, T128Q, R131K, T148C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDPK1, PDK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O15530, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 334 molecules

#2: Chemical ChemComp-S26 / ethyl (2~{S})-1-(6-chloranyl-1,3-benzothiazol-2-yl)-4-oxidanyl-5-oxidanylidene-2-thiophen-2-yl-2~{H}-pyrrole-3-carboxylate / PS267


Mass: 420.890 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H13ClN2O4S2
#3: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL / Dithiothreitol


Mass: 154.251 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2S2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 1
Mutation: K76S, L113V, I118V, I119N, V124I, T128Q, R131K, T148C
Source method: isolated from a genetically manipulated source
Formula: C10H16N5O13P3 / References: non-specific serine/threonine protein kinase / Comment: ATP, energy-carrying molecule*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 329 / 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: 2.17 Å3/Da / Density % sol: 43.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 1.2 M NA CITRATE, 0.1 M HEPES PH 7.5, 10 MM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 28, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.41→47 Å / Num. obs: 57639 / % possible obs: 97.1 % / Redundancy: 2.5 % / Net I/σ(I): 13

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3HRC

3hrc


Resolution: 1.41→46.772 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 17.61
RfactorNum. reflection% reflection
Rfree0.1742 2882 5 %
Rwork0.1402 --
obs0.1419 57631 97.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.41→46.772 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2282 0 39 329 2650
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012532
X-RAY DIFFRACTIONf_angle_d1.613471
X-RAY DIFFRACTIONf_dihedral_angle_d16.413972
X-RAY DIFFRACTIONf_chiral_restr0.097382
X-RAY DIFFRACTIONf_plane_restr0.009437
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4099-1.4330.27811340.24412547X-RAY DIFFRACTION96
1.433-1.45780.26411350.22282575X-RAY DIFFRACTION96
1.4578-1.48430.23951360.20672586X-RAY DIFFRACTION96
1.4843-1.51280.25791330.1772519X-RAY DIFFRACTION96
1.5128-1.54370.23091360.17162587X-RAY DIFFRACTION96
1.5437-1.57730.22341350.16252561X-RAY DIFFRACTION97
1.5773-1.6140.20921370.14992598X-RAY DIFFRACTION97
1.614-1.65430.22821380.14962624X-RAY DIFFRACTION97
1.6543-1.6990.20741350.14532561X-RAY DIFFRACTION97
1.699-1.7490.19761360.13612582X-RAY DIFFRACTION97
1.749-1.80550.17131380.13022629X-RAY DIFFRACTION98
1.8055-1.870.1631370.13212597X-RAY DIFFRACTION97
1.87-1.94490.1621360.11922598X-RAY DIFFRACTION98
1.9449-2.03340.15991390.12152625X-RAY DIFFRACTION98
2.0334-2.14060.14841370.11892604X-RAY DIFFRACTION98
2.1406-2.27470.17581390.11382642X-RAY DIFFRACTION98
2.2747-2.45040.15351390.12082645X-RAY DIFFRACTION98
2.4504-2.69690.1761390.13842643X-RAY DIFFRACTION98
2.6969-3.08710.17361390.14292636X-RAY DIFFRACTION97
3.0871-3.88920.15631400.13642655X-RAY DIFFRACTION97
3.8892-46.79740.15211440.14792735X-RAY DIFFRACTION98

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