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- PDB-7pue: Human serum and glucocorticoid-regulated kinase 1 in complex with... -

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Basic information

Entry
Database: PDB / ID: 7pue
TitleHuman serum and glucocorticoid-regulated kinase 1 in complex with pyrazolopyridine inhibitor 3a
ComponentsSerine/threonine-protein kinase Sgk1
KeywordsTRANSFERASE / serine/threonine protein kinase / atp-competitive inhibitor / DFG-loop / hinge-binder / osteoarthritis / cartilage degradation / pyrazolo-pyridine
Function / homology
Function and homology information


regulation of gastric acid secretion / renal sodium ion absorption / Transcriptional Regulation by MECP2 / positive regulation of transporter activity / cellular response to aldosterone / regulation of catalytic activity / NGF-stimulated transcription / chloride channel regulator activity / regulation of DNA-binding transcription factor activity / sodium ion transport ...regulation of gastric acid secretion / renal sodium ion absorption / Transcriptional Regulation by MECP2 / positive regulation of transporter activity / cellular response to aldosterone / regulation of catalytic activity / NGF-stimulated transcription / chloride channel regulator activity / regulation of DNA-binding transcription factor activity / sodium ion transport / calcium channel regulator activity / potassium channel regulator activity / sodium channel regulator activity / long-term memory / regulation of cell migration / protein serine/threonine/tyrosine kinase activity / neuron projection morphogenesis / regulation of signal transduction by p53 class mediator / regulation of cell growth / Stimuli-sensing channels / regulation of blood pressure / Regulation of TP53 Degradation / PIP3 activates AKT signaling / regulation of cell population proliferation / regulation of apoptotic process / non-specific serine/threonine protein kinase / intracellular signal transduction / nuclear speck / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / DNA damage response / endoplasmic reticulum membrane / mitochondrion / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Protein kinase, C-terminal / Protein kinase C terminal domain / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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 kinase, C-terminal / Protein kinase C terminal domain / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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
Similarity search - Domain/homology
Chem-86H / Serine/threonine-protein kinase Sgk1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.506 Å
AuthorsDreyer, M.K. / Halland, N. / Nazare, M.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2022
Title: Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis.
Authors: Halland, N. / Schmidt, F. / Weiss, T. / Li, Z. / Czech, J. / Saas, J. / Ding-Pfennigdorff, D. / Dreyer, M.K. / Strubing, C. / Nazare, M.
History
DepositionSep 29, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 1, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 2, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Feb 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.3May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine/threonine-protein kinase Sgk1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2274
Polymers42,5111
Non-polymers7163
Water43224
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area450 Å2
ΔGint0 kcal/mol
Surface area13830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.445, 92.445, 172.033
Angle α, β, γ (deg.)90, 90, 120
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein Serine/threonine-protein kinase Sgk1 / Serum/glucocorticoid-regulated kinase 1


Mass: 42511.488 Da / Num. of mol.: 1 / Mutation: R192A, S422D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SGK1, SGK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O00141, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-86H / 6-[4-[[2,3-bis(chloranyl)phenyl]sulfonylamino]phenyl]-~{N}-[(3~{R})-pyrrolidin-3-yl]-2~{H}-pyrazolo[3,4-b]pyridine-4-carboxamide


Mass: 531.414 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20Cl2N6O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.63 Å3/Da / Density % sol: 53.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: protein solution: 25 mM Hepes, 100 mM NaCl,1 mM DTT, 5 mM MgCl2 pH 7.8; 3 mM Amppnp; reservoir solution: 12% PEG3350, 200 mM NaF; soaking in res.sol.+ 10 mM Cpd3a, 10% DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 1, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.51→19.73 Å / Num. obs: 10904 / % possible obs: 92.9 % / Redundancy: 8.5 % / CC1/2: 1 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.038 / Rrim(I) all: 0.079 / Net I/σ(I): 19.3
Reflection shellResolution: 2.51→2.77 Å / Redundancy: 6.8 % / Rmerge(I) obs: 1.388 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 546 / CC1/2: 0.713 / Rpim(I) all: 0.541 / % possible all: 69.3

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSdata reduction
autoPROCdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: earlier in-house structure

Resolution: 2.506→19.73 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.918 / SU R Cruickshank DPI: 0.634 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.686 / SU Rfree Blow DPI: 0.316 / SU Rfree Cruickshank DPI: 0.316
RfactorNum. reflection% reflectionSelection details
Rfree0.2486 767 -RANDOM
Rwork0.2135 ---
obs0.2161 10904 70.1 %-
Displacement parametersBiso mean: 86.98 Å2
Baniso -1Baniso -2Baniso -3
1-3.7521 Å20 Å20 Å2
2--3.7521 Å20 Å2
3----7.5041 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: LAST / Resolution: 2.506→19.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2155 0 47 24 2226
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092263HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.153074HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d741SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes371HARMONIC5
X-RAY DIFFRACTIONt_it2263HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion281SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1760SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.26
X-RAY DIFFRACTIONt_other_torsion11.59
LS refinement shellResolution: 2.51→2.71 Å
RfactorNum. reflection% reflection
Rfree0.3479 23 -
Rwork0.3109 --
obs0.3142 287 9.19 %
Refinement TLS params.Origin x: -26.636 Å / Origin y: 26.2033 Å / Origin z: 1.454 Å
111213212223313233
T-0.0887 Å20.0509 Å20.0326 Å2--0.3699 Å20.0637 Å2---0.3826 Å2
L3.2019 °2-0.5842 °20.9468 °2-3.8399 °2-0.6138 °2--5.1137 °2
S0.0681 Å °-0.18 Å °-0.9301 Å °-0.18 Å °0.036 Å °-0.1308 Å °-0.9301 Å °-0.1308 Å °-0.1041 Å °
Refinement TLS groupSelection details: { A|* }

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