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- PDB-4aw0: Human PDK1 Kinase Domain in Complex with Allosteric Compound PS18... -

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Basic information

Entry
Database: PDB / ID: 4aw0
TitleHuman PDK1 Kinase Domain in Complex with Allosteric Compound PS182 Bound to the PIF-Pocket
Components3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1
KeywordsTRANSFERASE / ALLOSTERIC REGULATION / ALLOSTERIC SITE / PHOSPHORYLATION / AGC PROTEIN KINASE
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 / 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 / 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 / positive regulation of release of sequestered calcium ion into cytosol / insulin-like growth factor receptor signaling pathway / 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 / postsynaptic density / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation / focal adhesion / protein serine kinase activity / 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 / DITHIANE DIOL / Chem-MJF / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.43 Å
AuthorsSchulze, J.O. / Busschots, K. / Lopez-Garcia, L.A. / Lammi, C. / Stroba, A. / Zeuzem, S. / Piiper, A. / Alzari, P.M. / Neimanis, S. / Arencibia, J.M. ...Schulze, J.O. / Busschots, K. / Lopez-Garcia, L.A. / Lammi, C. / Stroba, A. / Zeuzem, S. / Piiper, A. / Alzari, P.M. / Neimanis, S. / Arencibia, J.M. / Engel, M. / Biondi, R.M.
CitationJournal: Chem.Biol. / Year: 2012
Title: Substrate-Selective Inhibition of Protein Kinase Pdk1 by Small Compounds that Bind to the Pif-Pocket Allosteric Docking Site.
Authors: Busschots, K. / Lopez-Garcia, L.A. / Lammi, C. / Stroba, A. / Zeuzem, S. / Piiper, A. / Alzari, P.M. / Neimanis, S. / Arencibia, J.M. / Engel, M. / Schulze, J.O. / Biondi, R.M.
History
DepositionMay 30, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 3, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 10, 2012Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Structure summary
Revision 2.0Dec 20, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Other / Refinement description
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_alt_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_alt_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 650 HELIX DETERMINATION METHOD: AUTHOR PROVIDED.
Remark 700 SHEET DETERMINATION METHOD: AUTHOR PROVIDED.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6027
Polymers35,4691
Non-polymers1,1336
Water4,089227
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)148.270, 44.010, 47.390
Angle α, β, γ (deg.)90.00, 101.57, 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: 35468.684 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 51-359 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O15530, non-specific serine/threonine protein kinase

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Non-polymers , 6 types, 233 molecules

#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-MJF / [(1R)-3-(4-chlorophenyl)-3-oxo-1-phenylpropyl]propanedioic acid


Mass: 346.762 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H15ClO5
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-DTD / DITHIANE DIOL


Mass: 152.235 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H8O2S2
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 227 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsENGINEERED RESIDUE IN CHAIN A, TYR 238 TO GLY ENGINEERED RESIDUE IN CHAIN A, GLN 242 TO ALA

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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: 2.3 Å3/Da / Density % sol: 47 % / Description: NONE
Crystal growpH: 7.5 / Details: 1.2 M NA CITRATE, 0.1 M HEPES PH 7.5, 0.01 M DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841
DetectorType: MARRESEARCH / Detector: CCD / Date: Jul 30, 2011 / Details: MIRRORS
RadiationMonochromator: SI-111 CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.43→46 Å / Num. obs: 53029 / % possible obs: 95.4 % / Observed criterion σ(I): 2.1 / Redundancy: 2.4 % / Biso Wilson estimate: 15.65 Å2 / Rmerge(I) obs: 0.03 / Net I/σ(I): 16.3
Reflection shellResolution: 1.43→1.53 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 2.1 / % possible all: 94.2

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3HRC

3hrc


Resolution: 1.43→46.427 Å / SU ML: 0.16 / σ(F): 1.99 / Phase error: 18.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1883 2651 5 %
Rwork0.1704 --
obs0.1714 53019 95.4 %
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 47.278 Å2 / ksol: 0.41 e/Å3
Displacement parametersBiso mean: 21.8 Å2
Baniso -1Baniso -2Baniso -3
1--0.3038 Å20 Å2-0.0753 Å2
2--1.6758 Å20 Å2
3----1.372 Å2
Refinement stepCycle: LAST / Resolution: 1.43→46.427 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2251 0 69 227 2547
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0142660
X-RAY DIFFRACTIONf_angle_d1.4453653
X-RAY DIFFRACTIONf_dihedral_angle_d15.3521027
X-RAY DIFFRACTIONf_chiral_restr0.088406
X-RAY DIFFRACTIONf_plane_restr0.008464
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4299-1.45590.29081360.28412574X-RAY DIFFRACTION94
1.4559-1.48390.27271360.2612585X-RAY DIFFRACTION94
1.4839-1.51420.2441420.23712692X-RAY DIFFRACTION97
1.5142-1.54710.22951320.2262520X-RAY DIFFRACTION92
1.5471-1.58310.23361440.20252722X-RAY DIFFRACTION97
1.5831-1.62270.19611400.19312678X-RAY DIFFRACTION98
1.6227-1.66660.24131420.18612698X-RAY DIFFRACTION98
1.6666-1.71560.23211420.18012690X-RAY DIFFRACTION98
1.7156-1.7710.20481420.17382706X-RAY DIFFRACTION98
1.771-1.83430.18261450.17232741X-RAY DIFFRACTION98
1.8343-1.90770.21561390.1692636X-RAY DIFFRACTION95
1.9077-1.99450.18321340.16152553X-RAY DIFFRACTION93
1.9945-2.09970.16971350.15172558X-RAY DIFFRACTION92
2.0997-2.23120.18441410.14982687X-RAY DIFFRACTION96
2.2312-2.40350.17411370.15352604X-RAY DIFFRACTION94
2.4035-2.64540.20121440.16432736X-RAY DIFFRACTION98
2.6454-3.02810.17491400.16462668X-RAY DIFFRACTION96
3.0281-3.81480.16561410.15472673X-RAY DIFFRACTION94
3.8148-46.45190.17361390.1712647X-RAY DIFFRACTION92
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.57670.0756-0.55081.14970.14482.20270.24240.21150.2311-0.0863-0.08920.1388-0.4271-0.2148-0.06280.13650.05870.02660.25990.04070.178-10.213627.5305-9.7869
21.68940.094-0.23241.3536-0.43431.26220.02890.06210.1236-0.0823-0.00260.0396-0.05440.09430.00010.0783-0.003-0.01230.066-0.01030.0678-21.291820.84773.4334
31.6773-0.20480.2171.6449-0.29891.2280.0335-0.1803-0.0765-0.01330.01950.3450.079-0.093-0.05980.123-0.006100.08650.00450.1657-35.109615.873910.4839
42.5769-0.1545-0.56141.63050.08041.7815-0.0368-0.2261-0.2240.16180.036-0.17310.18320.2643-0.00270.14250.0326-0.03960.18670.01680.1085-15.857914.470516.6318
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND (RESSEQ 75:150)
2X-RAY DIFFRACTION2CHAIN A AND (RESSEQ 151:277)
3X-RAY DIFFRACTION3CHAIN A AND (RESSEQ 278:327)
4X-RAY DIFFRACTION4CHAIN A AND (RESSEQ 328:359)

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