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- PDB-3pwy: Crystal structure of an extender (SPD28345)-modified human PDK1 c... -

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Basic information

Entry
Database: PDB / ID: 3pwy
TitleCrystal structure of an extender (SPD28345)-modified human PDK1 complex 2
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / fragment-based drug discovery / tethering with extenders / 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 / 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 / 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 / positive regulation of protein localization to plasma membrane / peptidyl-threonine phosphorylation / 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 / FCERI mediated NF-kB activation / cellular response to insulin stimulus / G beta:gamma signalling through PI3Kgamma / positive regulation of angiogenesis / Regulation of TP53 Degradation / cell migration / Downstream TCR signaling / insulin receptor signaling pathway / PIP3 activates AKT signaling / 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 / 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 ...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-SYP / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsElling, R.A. / Penny, D.M. / Simmons, R.L. / Erlanson, D.A. / Romanowski, M.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery.
Authors: Erlanson, D.A. / Arndt, J.W. / Cancilla, M.T. / Cao, K. / Elling, R.A. / English, N. / Friedman, J. / Hansen, S.K. / Hession, C. / Joseph, I. / Kumaravel, G. / Lee, W.C. / Lind, K.E. / ...Authors: Erlanson, D.A. / Arndt, J.W. / Cancilla, M.T. / Cao, K. / Elling, R.A. / English, N. / Friedman, J. / Hansen, S.K. / Hession, C. / Joseph, I. / Kumaravel, G. / Lee, W.C. / Lind, K.E. / McDowell, R.S. / Miatkowski, K. / Nguyen, C. / Nguyen, T.B. / Park, S. / Pathan, N. / Penny, D.M. / Romanowski, M.J. / Scott, D. / Silvian, L. / Simmons, R.L. / Tangonan, B.T. / Yang, W. / Sun, L.
History
DepositionDec 9, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 20, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / 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_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _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)35,7292
Polymers35,4601
Non-polymers2691
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)122.376, 122.376, 47.632
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: 35459.762 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 51-359) / Mutation: E166C, C260S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDK1, PDPK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O15530, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SYP / N-[2-({6-[(2-sulfanylethyl)amino]pyrimidin-4-yl}amino)ethyl]propanamide


Mass: 269.366 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H19N5OS
Nonpolymer detailsLIGAND SYP WAS N-{2-[6-(2-MERCAPTO-ETHYLAMINO)-PYRIMIDIN-4-YLAMINO]-ETHYL}-ACRYLAMIDE PRIOR TO ...LIGAND SYP WAS N-{2-[6-(2-MERCAPTO-ETHYLAMINO)-PYRIMIDIN-4-YLAMINO]-ETHYL}-ACRYLAMIDE PRIOR TO BECOMING COVALENTLY BOUND.

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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: 57.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 0.1 M Tris pH 7.4, 2.1 M ammonium sulfate; 16 mg/ml protein in 50 mM Tris pH 8, 400 mM KCl, 3 mM DTT; supplemented with 20 mM DTT prior to addition of inhibitor, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL1-5 / Wavelength: 0.98
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 12, 2006
Details: 1-m-long Rh-coated bent cylindrical mirror for horizontal and vertical focusing
RadiationMonochromator: Double-crystal, parallel monochromator; crystal type Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 3.5→100 Å / Num. all: 14428 / Num. obs: 5005 / % possible obs: 93.7 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 2.9 % / Rsym value: 0.135 / Net I/σ(I): 5.2

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.2.0005refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1H1W

1h1w


Resolution: 3.5→20 Å / Cor.coef. Fo:Fc: 0.884 / Cor.coef. Fo:Fc free: 0.822 / SU B: 34.64 / SU ML: 0.556 / Cross valid method: THROUGHOUT / ESU R Free: 0.73 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.27649 476 9.6 %RANDOM
Rwork0.22014 ---
obs0.22572 4491 93.38 %-
all-5005 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.27 Å2
Baniso -1Baniso -2Baniso -3
1-2.18 Å21.09 Å20 Å2
2--2.18 Å20 Å2
3----3.28 Å2
Refinement stepCycle: LAST / Resolution: 3.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2265 0 18 0 2283
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0222342
X-RAY DIFFRACTIONr_angle_refined_deg0.8681.9863161
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5985279
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.29523.431102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.67515410
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.8681513
X-RAY DIFFRACTIONr_chiral_restr0.0590.2344
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.021755
X-RAY DIFFRACTIONr_nbd_refined0.1710.21041
X-RAY DIFFRACTIONr_nbtor_refined0.30.21601
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1380.257
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1270.236
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2160.23
LS refinement shellResolution: 3.5→3.619 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.276 38 -
Rwork0.227 446 -
obs--96.03 %

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