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- PDB-6ol2: Crystallography of novel WNK1 and WNK3 inhibitors discovered from... -

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Basic information

Entry
Database: PDB / ID: 6ol2
TitleCrystallography of novel WNK1 and WNK3 inhibitors discovered from high-throughput-screening
ComponentsSerine/threonine-protein kinase WNK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of cell-cell adhesion mediated by integrin / lymphocyte migration into lymph node / chemokine (C-C motif) ligand 21 signaling pathway / monoatomic cation homeostasis / positive regulation of termination of RNA polymerase II transcription / negative regulation of pancreatic juice secretion / protein insertion into ER membrane by stop-transfer membrane-anchor sequence / negative regulation of small GTPase mediated signal transduction / monoatomic ion homeostasis / positive regulation of mitotic cytokinesis ...negative regulation of cell-cell adhesion mediated by integrin / lymphocyte migration into lymph node / chemokine (C-C motif) ligand 21 signaling pathway / monoatomic cation homeostasis / positive regulation of termination of RNA polymerase II transcription / negative regulation of pancreatic juice secretion / protein insertion into ER membrane by stop-transfer membrane-anchor sequence / negative regulation of small GTPase mediated signal transduction / monoatomic ion homeostasis / positive regulation of mitotic cytokinesis / negative regulation of sodium ion transport / positive regulation of potassium ion import across plasma membrane / regulation of mRNA export from nucleus / intracellular chloride ion homeostasis / negative regulation of heterotypic cell-cell adhesion / positive regulation of T cell chemotaxis / regulation of sodium ion transmembrane transport / potassium channel inhibitor activity / cellular response to chemokine / potassium ion homeostasis / negative regulation of leukocyte cell-cell adhesion / cellular hyperosmotic response / membraneless organelle assembly / cell volume homeostasis / regulation of monoatomic cation transmembrane transport / intracellular membraneless organelle / positive regulation of systemic arterial blood pressure / protein kinase activator activity / protein serine/threonine kinase inhibitor activity / negative regulation of protein localization to plasma membrane / phosphatase binding / regulation of sodium ion transport / monoatomic ion transport / negative regulation of protein ubiquitination / sodium ion transmembrane transport / negative regulation of autophagy / cellular response to calcium ion / molecular condensate scaffold activity / modulation of chemical synaptic transmission / GABA-ergic synapse / regulation of blood pressure / positive regulation of angiogenesis / mitotic spindle / positive regulation of canonical Wnt signaling pathway / T cell receptor signaling pathway / heart development / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / protein kinase binding / magnesium ion binding / signal transduction / protein-containing complex / ATP binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
: / WNK CCTL2 domain / : / Serine/threonine-protein kinase OSR1/WNK, CCT domain / Oxidative-stress-responsive kinase 1 C-terminal domain / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site ...: / WNK CCTL2 domain / : / Serine/threonine-protein kinase OSR1/WNK, CCT domain / Oxidative-stress-responsive kinase 1 C-terminal domain / 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 domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / Chem-MU7 / Serine/threonine-protein kinase WNK1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsChlebowicz, J. / Akella, R. / Sekulski, K. / Humphreys, J.M. / Durbacz, M.Z. / He, H. / Rodan, A. / Posner, B. / Goldsmith, E.J.
Funding support United States, 1items
OrganizationGrant numberCountry
American Heart Association16SA285300002 United States
CitationJournal: To Be Published
Title: Crystallography of novel WNK1 and WNK3 inhibitors discovered from high throughput screening
Authors: Chlebowicz, J. / Akella, R. / Sekulski, K. / Humphreys, J.M. / Durbacz, M.Z. / He, H. / Rodan, A. / Posner, B. / Goldsmith, E.J.
History
DepositionApr 15, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase WNK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5059
Polymers33,4811
Non-polymers1,0248
Water3,567198
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1170 Å2
ΔGint-2 kcal/mol
Surface area14900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.925, 60.204, 65.502
Angle α, β, γ (deg.)90.00, 93.05, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Serine/threonine-protein kinase WNK1 / Protein kinase lysine-deficient 1 / Protein kinase with no lysine 1


Mass: 33481.496 Da / Num. of mol.: 1 / Fragment: UNP residues 194-483 / Mutation: S382A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Wnk1, Hsn2, Prkwnk1 / Plasmid: pHis / Production host: Escherichia coli (E. coli)
References: UniProt: Q9JIH7, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-MU7 / N-[2-(5,8-dimethoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]-2-iodobenzamide


Mass: 478.280 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19IN2O4
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 198 / Source method: isolated from a natural source / Formula: H2O

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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: 2.4 Å3/Da / Density % sol: 48.75 % / Description: Plates
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 20% PEG3350, 0.2 M sodium formate

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Data collection

DiffractionMean temperature: 80 K / Ambient temp details: liquid nitrogen / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97905 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 18, 2018
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97905 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 18499 / % possible obs: 94.6 % / Redundancy: 3.4 % / Rsym value: 0.08 / Net I/σ(I): 24.1
Reflection shellHighest resolution: 2.1 Å / Redundancy: 2.4 % / Num. unique obs: 600 / Rsym value: 0.541 / % possible all: 94

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
HKL-3000data reduction
HKL-3000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5DRB

5drb


Resolution: 2.1→34.25 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.879 / SU B: 11.202 / SU ML: 0.154 / Cross valid method: THROUGHOUT / ESU R: 0.305 / ESU R Free: 0.238 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.26754 811 5 %RANDOM
Rwork0.20209 ---
obs0.20528 15346 90.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.844 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å20 Å20.09 Å2
2--0.04 Å2-0 Å2
3----0.01 Å2
Refinement stepCycle: 1 / Resolution: 2.1→34.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2236 0 63 198 2497
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0122336
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.5811.6623132
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.6735278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.04321.88117
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.51415437
X-RAY DIFFRACTIONr_dihedral_angle_4_deg25.5981516
X-RAY DIFFRACTIONr_chiral_restr0.0590.2300
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021730
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.4831.6781119
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.7272.481392
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it5.52.1611217
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined10.14823.9053703
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.299 45 -
Rwork0.204 953 -
obs--75.32 %
Refinement TLS params.Method: refined / Origin x: 4.5044 Å / Origin y: -0.448 Å / Origin z: 15.9866 Å
111213212223313233
T0.0826 Å20.0035 Å20.0059 Å2-0.1193 Å20.0083 Å2--0.0068 Å2
L0.4507 °20.0019 °2-0.259 °2-0.419 °2-0.3259 °2--0.7639 °2
S0.0082 Å °0.1991 Å °-0.0123 Å °0.1059 Å °-0.0745 Å °-0.0264 Å °0.0532 Å °0.0076 Å °0.0663 Å °

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