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- PDB-8edh: Identification of a class of WNK isoform-specific inhibitors thro... -

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Basic information

Entry
Database: PDB / ID: 8edh
TitleIdentification of a class of WNK isoform-specific inhibitors through high-throughput screening
ComponentsSerine/threonine-protein kinase WNK3
KeywordsTRANSFERASE / inhibitor / WNK3 / kinase / complex
Function / homology
Function and homology information


positive regulation of ion transmembrane transporter activity / negative regulation of pancreatic juice secretion / positive regulation of sodium ion transmembrane transporter activity / monoatomic ion homeostasis / non-membrane-bounded organelle assembly / regulation of calcium ion import / osmosensory signaling pathway / positive regulation of sodium ion transport / cellular hyperosmotic response / positive regulation of calcium ion transport ...positive regulation of ion transmembrane transporter activity / negative regulation of pancreatic juice secretion / positive regulation of sodium ion transmembrane transporter activity / monoatomic ion homeostasis / non-membrane-bounded organelle assembly / regulation of calcium ion import / osmosensory signaling pathway / positive regulation of sodium ion transport / cellular hyperosmotic response / positive regulation of calcium ion transport / regulation of monoatomic cation transmembrane transport / cell volume homeostasis / negative regulation of protein localization to plasma membrane / maintenance of blood-brain barrier / bicellular tight junction / molecular condensate scaffold activity / positive regulation of peptidyl-threonine phosphorylation / protein localization to plasma membrane / positive regulation of protein localization to plasma membrane / adherens junction / peptidyl-threonine phosphorylation / Stimuli-sensing channels / protein autophosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / negative regulation of apoptotic process / ATP binding / cytoplasm
Similarity search - Function
Serine/threonine-protein kinase OSR1/WNK, CCT domain / Oxidative-stress-responsive kinase 1 C-terminal domain / 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
Similarity search - Domain/homology
Chem-WGK / Serine/threonine-protein kinase WNK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.111 Å
AuthorsAkella, R. / Goldsmith, E.J.
Funding support United States, 1items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)RP190421 United States
CitationJournal: Drug Des Devel Ther / Year: 2023
Title: Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening.
Authors: Chlebowicz, J. / Akella, R. / Humphreys, J.M. / He, H. / Kannangara, A.R. / Wei, S. / Posner, B. / Goldsmith, E.J.
History
DepositionSep 4, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 1, 2023Provider: repository / Type: Initial release
Revision 2.0Apr 26, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Database references / Derived calculations / Polymer sequence / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / entity ...atom_site / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_conf / struct_mon_prot_cis / struct_ncs_dom_lim / struct_ref / struct_ref_seq / struct_ref_seq_dif / struct_sheet_range
Item: _atom_site.label_seq_id / _entity.formula_weight ..._atom_site.label_seq_id / _entity.formula_weight / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.pdbx_end_seq_num / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_unobs_or_zero_occ_atoms.label_seq_id / _struct_conf.beg_label_seq_id / _struct_conf.end_label_seq_id / _struct_mon_prot_cis.label_seq_id / _struct_mon_prot_cis.pdbx_label_seq_id_2 / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.seq_align_end / _struct_ref_seq_dif.seq_num / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id
Revision 2.1Oct 25, 2023Group: 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

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase WNK3
C: Serine/threonine-protein kinase WNK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,6343
Polymers67,2762
Non-polymers3581
Water2,846158
1
A: Serine/threonine-protein kinase WNK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9962
Polymers33,6381
Non-polymers3581
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Serine/threonine-protein kinase WNK3


Theoretical massNumber of molelcules
Total (without water)33,6381
Polymers33,6381
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.976, 112.473, 66.642
Angle α, β, γ (deg.)90.000, 100.268, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21A

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: ALA / End label comp-ID: ALA / Refine code: 1 / Auth asym-ID: A / Label asym-ID: A / Auth seq-ID: 137 - 406 / Label seq-ID: 20 - 289

Dom-ID
1
2

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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Components

#1: Protein Serine/threonine-protein kinase WNK3 / Protein kinase lysine-deficient 3 / Protein kinase with no lysine 3


Mass: 33637.930 Da / Num. of mol.: 2 / Mutation: S308A
Source method: isolated from a genetically manipulated source
Details: Kinase domain of WNK3 with S308A mutation / Source: (gene. exp.) Homo sapiens (human) / Gene: WNK3, KIAA1566, PRKWNK3 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: Q9BYP7, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-WGK / ethyl 1-(5,7-dimethoxy-4-methylquinolin-2-yl)piperidine-4-carboxylate


Mass: 358.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H26N2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 158 / 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: 2.78 Å3/Da / Density % sol: 56 % / Description: plates
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.1M Sodium Malonate pH 5.0 and 12% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97925 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97925 Å / Relative weight: 1
ReflectionResolution: 3.11→27.8 Å / Num. obs: 13357 / % possible obs: 86 % / Redundancy: 4.8 % / Biso Wilson estimate: 44.4 Å2 / CC1/2: 0.95 / Rpim(I) all: 0.04 / Rsym value: 0.07 / Net I/σ(I): 8.4
Reflection shellResolution: 3.11→4.8 Å / Redundancy: 4.9 % / Num. unique obs: 674 / CC1/2: 0.4 / % possible all: 98.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
HKL-3000data reduction
HKL-3000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FPQ

5fpq


Resolution: 3.111→26.485 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.814 / WRfactor Rfree: 0.285 / WRfactor Rwork: 0.178 / SU B: 27.783 / SU ML: 0.457 / Average fsc free: 0.9415 / Average fsc work: 0.9742 / Cross valid method: FREE R-VALUE / ESU R Free: 0.665 / Details: Hydrogens have not been used
RfactorNum. reflection% reflectionSelection details
Rfree0.2911 1046 9.634 %10%
Rwork0.1857 9811 --
all0.196 ---
obs-10857 81.301 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 69.718 Å2
Baniso -1Baniso -2Baniso -3
1-0.239 Å20 Å20.213 Å2
2---1.259 Å2-0 Å2
3---0.884 Å2
Refinement stepCycle: LAST / Resolution: 3.111→26.485 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4126 0 26 158 4310
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0124239
X-RAY DIFFRACTIONr_angle_refined_deg1.3911.6545709
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7575511
X-RAY DIFFRACTIONr_dihedral_angle_2_deg15.5111024
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.82910791
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.7710180
X-RAY DIFFRACTIONr_chiral_restr0.0970.2630
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023082
X-RAY DIFFRACTIONr_nbd_refined0.2450.22168
X-RAY DIFFRACTIONr_nbtor_refined0.3140.22876
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1650.2159
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2530.222
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2020.23
X-RAY DIFFRACTIONr_mcbond_it5.676.8642059
X-RAY DIFFRACTIONr_mcangle_it9.4510.2742566
X-RAY DIFFRACTIONr_scbond_it6.4477.3252180
X-RAY DIFFRACTIONr_scangle_it10.26410.7973143
X-RAY DIFFRACTIONr_lrange_it19.552130.26217765
X-RAY DIFFRACTIONr_ncsr_local_group_10.1730.057596
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.172750.05007
12AX-RAY DIFFRACTIONLocal ncs0.172750.05007
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
3.111-3.190.379200.252170.269860.90.96124.03650.232
3.19-3.2770.349370.2823250.299300.9290.94938.92470.258
3.277-3.370.381420.2824650.2929280.9080.94754.63360.25
3.37-3.4720.271520.2745490.2748810.9370.95368.21790.236
3.472-3.5840.348730.2475810.268620.9170.96175.87010.216
3.584-3.7070.353650.2286440.248510.9160.96783.31380.199
3.707-3.8440.338520.2187390.2278060.9240.9798.1390.192
3.844-3.9980.28830.1917010.27880.9450.97799.49240.172
3.998-4.1710.323850.1836600.1997480.9290.97999.59890.159
4.171-4.3690.247600.1676500.1747130.9580.98299.57920.155
4.369-4.5990.258720.1456130.1576880.960.98699.5640.139
4.599-4.8690.267640.1475680.1596460.9570.98697.83280.14
4.869-5.1920.245730.135310.1436150.9670.9998.21140.133
5.192-5.590.292550.1515050.1655870.9540.98695.40030.151
5.59-6.0970.283520.1774570.1895130.9560.98299.22030.182
6.097-6.7720.364490.1944290.2114810.9280.97999.37630.199
6.772-7.7350.233370.1553920.1624320.9730.98499.30560.172
7.735-9.2780.206270.1343430.1393730.9760.98999.19570.174
9.278-12.3830.308290.1782610.193040.9430.98395.39470.22
12.383-26.4850.255190.2491810.2492000.9440.9531000.327

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