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- PDB-3sc1: Novel Isoquinolone PDK1 Inhibitors Discovered through Fragment-Ba... -

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Basic information

Entry
Database: PDB / ID: 3sc1
TitleNovel Isoquinolone PDK1 Inhibitors Discovered through Fragment-Based Lead Discovery
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE DOMAIN / PHOSPHOSERINE / SEP / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


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 / positive regulation of vascular endothelial cell proliferation / negative regulation of cardiac muscle cell apoptotic process ...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 / 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 / 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 / vascular endothelial cell response to laminar fluid shear stress / negative regulation of endothelial cell apoptotic process / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / activation of protein kinase B activity / 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 / Integrin signaling / peptidyl-threonine phosphorylation / cellular response to epidermal growth factor stimulus / insulin-like growth factor receptor signaling pathway / positive regulation of release of sequestered calcium ion into cytosol / VEGFR2 mediated cell proliferation / VEGFR2 mediated vascular permeability / cell projection / positive regulation of protein localization to plasma membrane / phosphatidylinositol 3-kinase/protein kinase B signal transduction / negative regulation of transforming growth factor beta receptor signaling pathway / calcium-mediated signaling / CLEC7A (Dectin-1) signaling / epidermal growth factor receptor signaling pathway / FCERI mediated NF-kB activation / cellular response to insulin stimulus / positive regulation of angiogenesis / G beta:gamma signalling through PI3Kgamma / Regulation of TP53 Degradation / insulin receptor signaling pathway / Downstream TCR signaling / cell migration / PIP3 activates AKT signaling / actin cytoskeleton organization / protein autophosphorylation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cytoplasmic vesicle / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / postsynaptic density / 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 / 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
6-[2-(hydroxymethyl)phenyl]isoquinolin-1(2H)-one / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.7 Å
AuthorsGreasley, S.E. / Ferre, R.-A. / Krauss, M. / Cronin, C.
CitationJournal: J Comput Aided Mol Des / Year: 2011
Title: Novel isoquinolone PDK1 inhibitors discovered through fragment-based lead discovery.
Authors: Johnson, M.C. / Hu, Q. / Lingardo, L. / Ferre, R.A. / Greasley, S. / Yan, J. / Kath, J. / Chen, P. / Ermolieff, J. / Alton, G.
History
DepositionJun 6, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 26, 2011Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2017Group: Refinement description / Category: software
Revision 1.2Nov 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 / citation / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_ref_seq_dif / struct_site
Item: _citation.country / _citation.journal_id_ISSN ..._citation.country / _citation.journal_id_ISSN / _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

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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)36,3758
Polymers35,5561
Non-polymers8207
Water55831
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: 3-phosphoinositide-dependent protein kinase 1
hetero molecules

A: 3-phosphoinositide-dependent protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,75116
Polymers71,1112
Non-polymers1,63914
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_556y,x,-z+11
Buried area4840 Å2
ΔGint-142 kcal/mol
Surface area24540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)123.707, 123.707, 47.295
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: 35555.738 Da / Num. of mol.: 1 / Fragment: Protein kinase domain, residues 50-359
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
#2: Chemical ChemComp-3S1 / 6-[2-(hydroxymethyl)phenyl]isoquinolin-1(2H)-one


Mass: 251.280 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13NO2
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / 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: 2.94 Å3/Da / Density % sol: 58.14 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 2.2M AMMONIUM SULFATE, 10MM EDTA, 5-% GLYCEROL, 0.1M HEPES, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.99 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 25, 2008 / Details: mirrors
RadiationMonochromator: DOUBLE-CRYSTAL, SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99 Å / Relative weight: 1
ReflectionResolution: 2.65→50 Å / Num. all: 12487 / Num. obs: 12487 / % possible obs: 99.9 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 4.13 % / Rsym value: 0.146 / Net I/σ(I): 11.9
Reflection shellResolution: 2.65→2.7 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 1.3 / Num. unique all: 609 / Rsym value: 0.88 / % possible all: 99.8

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Processing

Software
NameClassification
HKL-2000data collection
REFMACrefinement
ARPmodel building
WARPmodel building
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.7→50 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.2371 537 RANDOM
Rwork0.1999 --
all0.1999 10969 -
obs0.1999 10432 -
Refinement stepCycle: LAST / Resolution: 2.7→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2285 0 51 31 2367

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