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- PDB-1z5m: Crystal Structure Of N1-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbon... -

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Basic information

Entry
Database: PDB / ID: 1z5m
TitleCrystal Structure Of N1-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl)amino]phenyl]amino]-4-pyrimidinyl]amino]propyl]-2,2-dimethylpropanediamide Complexed with Human PDK1
Components3-phosphoinositide dependent protein kinase-1
KeywordsTRANSFERASE / PROTEIN INHIBITOR COMPLEX / SERINE KINASE
Function / homology
Function and homology information


intracellular signaling cassette / 3-phosphoinositide-dependent protein kinase activity / Activation of AKT2 / regulation of mast cell degranulation / type B pancreatic cell development / negative regulation of toll-like receptor signaling pathway / RSK activation / positive regulation of vascular endothelial cell proliferation / regulation of canonical NF-kappaB signal transduction / phospholipase activator activity ...intracellular signaling cassette / 3-phosphoinositide-dependent protein kinase activity / Activation of AKT2 / regulation of mast cell degranulation / type B pancreatic cell development / negative regulation of toll-like receptor signaling pathway / RSK activation / positive regulation of vascular endothelial cell proliferation / regulation of canonical NF-kappaB signal transduction / phospholipase activator activity / positive regulation of sprouting angiogenesis / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of endothelial cell apoptotic process / negative regulation of cardiac muscle cell apoptotic process / Role of LAT2/NTAL/LAB on calcium mobilization / CD28 dependent PI3K/Akt signaling / positive regulation of blood vessel endothelial cell migration / extrinsic apoptotic signaling pathway / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / T cell costimulation / vascular endothelial cell response to laminar fluid shear stress / Estrogen-stimulated signaling through PRKCZ / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / GPVI-mediated activation cascade / insulin-like growth factor receptor signaling pathway / phospholipase binding / Integrin signaling / cell projection / cellular response to epidermal growth factor stimulus / positive regulation of release of sequestered calcium ion into cytosol / negative regulation of transforming growth factor beta receptor signaling pathway / phosphatidylinositol 3-kinase/protein kinase B signal transduction / VEGFR2 mediated vascular permeability / VEGFR2 mediated cell proliferation / calcium-mediated signaling / positive regulation of protein localization to plasma membrane / insulin receptor signaling pathway / epidermal growth factor receptor signaling pathway / CLEC7A (Dectin-1) signaling / positive regulation of angiogenesis / FCERI mediated NF-kB activation / actin cytoskeleton organization / cellular response to insulin stimulus / Regulation of TP53 Degradation / PIP3 activates AKT signaling / protein autophosphorylation / Downstream TCR signaling / cell migration / G beta:gamma signalling through PI3Kgamma / cytoplasmic vesicle / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein phosphorylation / non-specific serine/threonine protein kinase / postsynaptic density / intracellular signal transduction / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / DNA-templated transcription / 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
Chem-LI8 / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 Å
AuthorsWhitlow, M. / Adler, M.
Citation
Journal: J.Biol.Chem. / Year: 2005
Title: Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1.
Authors: Feldman, R.I. / Wu, J.M. / Polokoff, M.A. / Kochanny, M.J. / Dinter, H. / Zhu, D. / Biroc, S.L. / Alicke, B. / Bryant, J. / Yuan, S. / Buckman, B.O. / Lentz, D. / Ferrer, M. / Whitlow, M. / ...Authors: Feldman, R.I. / Wu, J.M. / Polokoff, M.A. / Kochanny, M.J. / Dinter, H. / Zhu, D. / Biroc, S.L. / Alicke, B. / Bryant, J. / Yuan, S. / Buckman, B.O. / Lentz, D. / Ferrer, M. / Whitlow, M. / Adler, M. / Finster, S. / Chang, Z. / Arnaiz, D.O.
#1: Journal: Embo J. / Year: 2002
Title: High Resolution Crystal Structure of the Human Pdk1 Catalytic Domain Defines the Regulatory Phosphopeptide Docking Site
Authors: Biondi, R.M. / Komander, D. / Thomas, C.C. / Lizcano, J.M. / Deak, M. / Alessi, D.R. / Van Aalten, D.M.F.
History
DepositionMar 18, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 19, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Aug 23, 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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature
Remark 600HETEROGEN THE INHIBITION CONSTANT (KI APPARENT) FOR N-(3-{[5-BROMO-2-({3-[(PYRROLIDIN-1- YLCARBONYL) ...HETEROGEN THE INHIBITION CONSTANT (KI APPARENT) FOR N-(3-{[5-BROMO-2-({3-[(PYRROLIDIN-1- YLCARBONYL)AMINO]PHENYL}AMINO)PYRIMIDIN -4-YL]AMINO}PROPYL)-2,2-DIMETHYLMALONAMIDE AGAINST PDK1 WAS MEASURED AS 30 NM (N=5) DIRECT MEASURE PDK1 ACTIVITY WAS PERFORMED BY THE FOLLOWING PROTOCOL: THE FINAL ASSAY MIXTURE (60 UL) CONTAINED 50 MM TRIS- HCL, PH 7.5, 0.1 MM EGTA, 0.1 MM EDTA, 0.1% BETA-MERCAPTOETHANOL, 1 MG/ML BOVINE SERUM ALBUMIN, 10 MM MGOAC, 10 UM ATP, 0.2 UCI OF [GAMMA-33P]ATP, 7.5 UM OF SUBSTRATE PEPTIDE (H2NARRRGVTTKTFCGT) AND 60 NG OF PURIFIED RECOMBINANT HUMAN PDK1. AFTER 4 H AT ROOM TEMPERATURE, WE ADDED 25 MM EDTA AND SPOTTED A PORTION OF THE REACTION MIXTURE ON WHATMAN P81 PHOSPHOCELLULOSE PAPER. THE FILTER PAPER WAS WASHED 3 TIMES WITH 0.75% PHOSPHORIC ACID AND ONCE WITH ACETONE. AFTER DRYING, THE FILTER-BOUND LABELED PEPTIDE WAS QUANTIFIED USING A FUJI PHOSPHOIMAGER.

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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)34,0857
Polymers33,1301
Non-polymers9556
Water1,33374
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)124.61, 124.61, 46.97
Angle α, β, γ (deg.)90.0, 90.0, 120.0
Int Tables number154
Space group name H-MP3221

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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: 33130.117 Da / Num. of mol.: 1 / Fragment: Kinase Domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDPK1, PDK1 / Plasmid: PDK1-CAT-PBB4.5 / Production host: unidentified baculovirus / Strain (production host): SF-21 cells / References: UniProt: O15530, EC: 2.7.1.37

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Non-polymers , 5 types, 80 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-LI8 / N-(3-{[5-BROMO-2-({3-[(PYRROLIDIN-1-YLCARBONYL)AMINO]PHENYL}AMINO)PYRIMIDIN-4-YL]AMINO}PROPYL)-2,2-DIMETHYLMALONAMIDE


Mass: 547.448 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H31BrN8O3
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.2 Å3/Da / Density % sol: 62 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Ammonium Sulfate, Tris, EDTA, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 94.2 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jun 22, 2003
RadiationMonochromator: single crystal Si(220); cylindrically bent / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.17→20 Å / Num. all: 22440 / Num. obs: 21597 / % possible obs: 96.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.417 % / Biso Wilson estimate: 36.4 Å2 / Rsym value: 0.0874 / Net I/σ(I): 8.33
Reflection shellResolution: 2.17→2.31 Å / Redundancy: 2.77 % / Mean I/σ(I) obs: 2.14 / Num. unique all: 3380 / Rsym value: 0.347 / % possible all: 91.2

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Processing

Software
NameVersionClassification
Blu-Icedata collection
X-GENdata reduction
MOLREPphasing
X-PLOR3.1refinement
X-GENdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDK1 Homology model built from pdb entry 1O6L

1o6l


Resolution: 2.17→8 Å / Isotropic thermal model: Overall / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.269 915 -RANDOM
Rwork0.212 ---
all0.232 22377 --
obs0.219 21580 96.4 %-
Displacement parametersBiso mean: 25.7 Å2
Baniso -1Baniso -2Baniso -3
1-1.18 Å21.61 Å20 Å2
2--1.18 Å20 Å2
3----2.35 Å2
Refinement stepCycle: LAST / Resolution: 2.17→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2255 0 59 74 2388
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.012
X-RAY DIFFRACTIONx_angle_deg1.77
X-RAY DIFFRACTIONx_improper_angle_d1.46
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkRefine-IDNum. reflection obs% reflection obs (%)
2.17-2.270.373850.309X-RAY DIFFRACTION209490
2.27-2.380.331100.29X-RAY DIFFRACTION238095.9
2.38-2.530.3181030.268X-RAY DIFFRACTION252998.2
2.53-2.720.341240.251X-RAY DIFFRACTION261098.6
2.72-2.980.2551200.222X-RAY DIFFRACTION262897.9
2.98-3.380.2651070.201X-RAY DIFFRACTION263697.6
3.38-4.150.221180.163X-RAY DIFFRACTION267797.6
4.15-80.235900.179X-RAY DIFFRACTION267595.7

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