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- PDB-6qj7: Difluorophenyl diacylhydrazides: Potent inhibitors of Serum- and ... -

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Basic information

Entry
Database: PDB / ID: 6qj7
TitleDifluorophenyl diacylhydrazides: Potent inhibitors of Serum- and Glucocorticoid-inducible Kinase 1 (SGK1)
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsTRANSFERASE / cAMP-dependent protein kinase A (PKA)
Function / homology
Function and homology information


PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / HDL assembly / negative regulation of cAMP-dependent protein kinase activity / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction ...PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / HDL assembly / negative regulation of cAMP-dependent protein kinase activity / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction / high-density lipoprotein particle assembly / Rap1 signalling / intracellular potassium ion homeostasis / negative regulation of cAMP/PKA signal transduction / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / regulation of protein processing / Loss of phosphorylation of MECP2 at T308 / cAMP-dependent protein kinase activity / CREB1 phosphorylation through the activation of Adenylate Cyclase / protein localization to lipid droplet / PKA activation / cAMP-dependent protein kinase complex / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / negative regulation of interleukin-2 production / negative regulation of protein import into nucleus / cellular response to cold / regulation of osteoblast differentiation / sperm capacitation / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / Triglyceride catabolism / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / mesoderm formation / cAMP/PKA signal transduction / RET signaling / Regulation of MECP2 expression and activity / sperm flagellum / Interleukin-3, Interleukin-5 and GM-CSF signaling / PKA activation in glucagon signalling / plasma membrane raft / DARPP-32 events / regulation of cardiac conduction / regulation of macroautophagy / regulation of cardiac muscle contraction / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / postsynaptic modulation of chemical synaptic transmission / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / Hedgehog 'off' state / positive regulation of phagocytosis / Ion homeostasis / regulation of G2/M transition of mitotic cell cycle / negative regulation of TORC1 signaling / regulation of proteasomal protein catabolic process / cellular response to epinephrine stimulus / sperm midpiece / calcium channel complex / Mitochondrial protein degradation / positive regulation of gluconeogenesis / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / CD209 (DC-SIGN) signaling / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / FCGR3A-mediated IL10 synthesis / positive regulation of calcium-mediated signaling / regulation of heart rate / protein export from nucleus / acrosomal vesicle / AURKA Activation by TPX2 / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / Regulation of insulin secretion / neural tube closure / Degradation of GLI1 by the proteasome / positive regulation of cholesterol biosynthetic process / cellular response to glucose stimulus / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cytokine-mediated signaling pathway / MAPK6/MAPK4 signaling / neuromuscular junction / positive regulation of insulin secretion / VEGFA-VEGFR2 Pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / mRNA processing / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / Regulation of PLK1 Activity at G2/M Transition / GPER1 signaling / peptidyl-serine phosphorylation / manganese ion binding
Similarity search - Function
cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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-J4B / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsGraedler, U.
CitationJournal: To Be Published
Title: Difluorophenyl diacylhydrazides: Potent inhibitors of Serum- and Glucocorticoid-inducible Kinase 1 (SGK1)
Authors: Graedler, U.
History
DepositionJan 23, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 12, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name
Revision 1.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: cAMP-dependent protein kinase catalytic subunit alpha
B: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,3993
Polymers43,0352
Non-polymers3641
Water6,089338
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1940 Å2
ΔGint-3 kcal/mol
Surface area16730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.359, 75.881, 79.968
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein cAMP-dependent protein kinase catalytic subunit alpha / PKA C-alpha


Mass: 40808.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKACA, PKACA / Production host: Escherichia coli (E. coli) / References: UniProt: P17612, cAMP-dependent protein kinase
#2: Protein/peptide cAMP-dependent protein kinase inhibitor alpha / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform


Mass: 2226.411 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: cAMP-dependent protein kinase inhibitor alpha / Source: (gene. exp.) Homo sapiens (human) / Gene: PKIA, PRKACN1 / Production host: Escherichia coli (E. coli) / References: UniProt: P61925
#3: Chemical ChemComp-J4B / ~{N}'-[(2~{S})-2-[3,5-bis(fluoranyl)phenyl]-2-oxidanyl-ethanoyl]-2-ethyl-3-methyl-4-oxidanyl-benzohydrazide


Mass: 364.343 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18F2N2O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 338 / 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: 2.57 Å3/Da / Density % sol: 52.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 5mM MES, 5mM Bis-Tris-propane, 75mM LiCl, 1mM DTT, 0.1mM EDTA, 1.4mM PKA-peptide, 1.4mM MEGA-8, 14% Et-OH as well solution

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X1A / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Aug 23, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.68→55.044 Å / Num. obs: 46905 / % possible obs: 96.4 % / Redundancy: 5.6 % / Biso Wilson estimate: 34.12 Å2 / Rmerge(I) obs: 0.2 / Net I/σ(I): 8.89
Reflection shellResolution: 1.68→1.78 Å / Rmerge(I) obs: 0.63 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 5872 / % possible all: 71.4

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
TRUNCATEdata reduction
autoPROC1.1.7data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ATP

1atp


Resolution: 1.69→52.37 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.951 / SU R Cruickshank DPI: 0.127 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.136 / SU Rfree Blow DPI: 0.126 / SU Rfree Cruickshank DPI: 0.122
RfactorNum. reflection% reflectionSelection details
Rfree0.214 1870 5.15 %RANDOM
Rwork0.178 ---
obs0.179 36337 72.2 %-
Displacement parametersBiso mean: 41.29 Å2
Baniso -1Baniso -2Baniso -3
1-1.5022 Å20 Å20 Å2
2---0.3599 Å20 Å2
3----1.1424 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: 1 / Resolution: 1.69→52.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2920 0 47 338 3305
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0123059HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.044131HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1071SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes513HARMONIC5
X-RAY DIFFRACTIONt_it3059HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion18.14
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion378SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3766SEMIHARMONIC4
LS refinement shellResolution: 1.69→1.79 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.227 -4.81 %
Rwork0.2358 692 -
all0.2353 727 -
obs--8.67 %
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)
11.04950.2809-0.08521.5724-0.67532.6834-0.01140.08120.03550.15220.00570.1751-0.4906-0.16420.0056-0.07670.0393-0.0003-0.093-0.0346-0.1175-27.433-2.18662.6425
21.04290.1640.05771.5615-0.76293.91960.01430.0244-0.15640.0583-0.07840.02810.02550.07630.06410.0588-0.0408-0.0261-0.01330.0103-0.063-13.54520.9481-8.6637
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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