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- PDB-5we8: Crystal structure of WNK1 in complex with N-{(3R)-1-[(4-chlorophe... -

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Basic information

Entry
Database: PDB / ID: 5we8
TitleCrystal structure of WNK1 in complex with N-{(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl}-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide (compound 8)
ComponentsSerine/threonine-protein kinase WNK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / 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 / positive regulation of termination of RNA polymerase II transcription / monoatomic cation homeostasis / negative regulation of pancreatic juice secretion / protein insertion into ER membrane by stop-transfer membrane-anchor sequence / positive regulation of mitotic cytokinesis / negative regulation of sodium ion transport / regulation of mRNA export from nucleus ...negative regulation of cell-cell adhesion mediated by integrin / lymphocyte migration into lymph node / chemokine (C-C motif) ligand 21 signaling pathway / positive regulation of termination of RNA polymerase II transcription / monoatomic cation homeostasis / negative regulation of pancreatic juice secretion / protein insertion into ER membrane by stop-transfer membrane-anchor sequence / positive regulation of mitotic cytokinesis / negative regulation of sodium ion transport / regulation of mRNA export from nucleus / regulation of sodium ion transmembrane transport / intracellular chloride ion homeostasis / negative regulation of heterotypic cell-cell adhesion / non-membrane-bounded organelle assembly / positive regulation of T cell chemotaxis / positive regulation of systemic arterial blood pressure / potassium ion homeostasis / cellular hyperosmotic response / cellular response to chemokine / negative regulation of leukocyte cell-cell adhesion / regulation of monoatomic cation transmembrane transport / cell volume homeostasis / negative regulation of protein localization to plasma membrane / negative regulation of GTPase activity / intracellular non-membrane-bounded organelle / protein kinase activator activity / sodium ion transmembrane transport / neuron development / phosphatase binding / monoatomic ion transport / regulation of sodium ion transport / negative regulation of protein ubiquitination / molecular condensate scaffold activity / negative regulation of autophagy / peptidyl-threonine phosphorylation / Stimuli-sensing channels / mitotic spindle / positive regulation of canonical Wnt signaling pathway / positive regulation of angiogenesis / heart development / T cell receptor signaling pathway / peptidyl-serine phosphorylation / 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 / signal transduction / protein-containing complex / ATP binding / membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
Serine/threonine-protein kinase OSR1/WNK, CCT domain / Oxidative-stress-responsive kinase 1 C-terminal domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Serine/threonine-protein kinase OSR1/WNK, CCT domain / Oxidative-stress-responsive kinase 1 C-terminal domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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
Chem-A7Y / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / : / Serine/threonine-protein kinase WNK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.006 Å
AuthorsXie, X. / Kohls, D.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension Models.
Authors: Yamada, K. / Levell, J. / Yoon, T. / Kohls, D. / Yowe, D. / Rigel, D.F. / Imase, H. / Yuan, J. / Yasoshima, K. / DiPetrillo, K. / Monovich, L. / Xu, L. / Zhu, M. / Kato, M. / Jain, M. / ...Authors: Yamada, K. / Levell, J. / Yoon, T. / Kohls, D. / Yowe, D. / Rigel, D.F. / Imase, H. / Yuan, J. / Yasoshima, K. / DiPetrillo, K. / Monovich, L. / Xu, L. / Zhu, M. / Kato, M. / Jain, M. / Idamakanti, N. / Taslimi, P. / Kawanami, T. / Argikar, U.A. / Kunjathoor, V. / Xie, X. / Yagi, Y.I. / Iwaki, Y. / Robinson, Z. / Park, H.M.
History
DepositionJul 7, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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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
B: Serine/threonine-protein kinase WNK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,8828
Polymers63,7882
Non-polymers2,0946
Water4,756264
1
A: Serine/threonine-protein kinase WNK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9414
Polymers31,8941
Non-polymers1,0473
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase WNK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9414
Polymers31,8941
Non-polymers1,0473
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)83.102, 105.235, 70.105
Angle α, β, γ (deg.)90.000, 117.280, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-699-

HOH

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Components

#1: Protein Serine/threonine-protein kinase WNK1 / Erythrocyte 65 kDa protein / p65 / Kinase deficient protein / Protein kinase lysine-deficient 1 / ...Erythrocyte 65 kDa protein / p65 / Kinase deficient protein / Protein kinase lysine-deficient 1 / Protein kinase with no lysine 1 / hWNK1


Mass: 31893.912 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WNK1, HSN2, KDP, KIAA0344, PRKWNK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9H4A3, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-A7Y / N-{(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl}-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide


Mass: 486.005 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H28ClN3O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 264 / 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: 2.14 Å3/Da / Density % sol: 42.4 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: co-crystallization of 10 mg/mL protein, 0.5 mM AMP-PNP, 1.5 mM manganese(II) chloride, 1 mM compound in crystallization reservoir solution (100 mM HEPES, pH 7.5, 15-17% PEG3350, 100-300 mM calcium acetate)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 15, 2008
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 34796 / % possible obs: 97.3 % / Redundancy: 3.7 % / Biso Wilson estimate: 31.04 Å2 / Rmerge(I) obs: 0.053 / Χ2: 1.038 / Net I/σ(I): 13.2 / Num. measured all: 129974
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsΧ2Diffraction-ID% possible all
2-2.072.90.2780.959187.5
2.07-2.153.50.2581.021197.3
2.15-2.253.70.2391.072197.8
2.25-2.373.90.181.045198.1
2.37-2.523.90.1221.013198.3
2.52-2.713.90.0910.989198.5
2.71-2.993.90.0650.944198.8
2.99-3.423.90.051.106199
3.42-4.313.90.0391.365199.1
2-2.072.90.2780.959187.5

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
RefinementResolution: 2.006→41.084 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.79
RfactorNum. reflection% reflection
Rfree0.2466 1731 4.98 %
Rwork0.2025 --
obs0.2047 34750 96.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 92.44 Å2 / Biso mean: 40.0299 Å2 / Biso min: 16.03 Å2
Refinement stepCycle: final / Resolution: 2.006→41.084 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4343 0 134 264 4741
Biso mean--46.28 43.45 -
Num. residues----542
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044578
X-RAY DIFFRACTIONf_angle_d0.7136180
X-RAY DIFFRACTIONf_chiral_restr0.046673
X-RAY DIFFRACTIONf_plane_restr0.004764
X-RAY DIFFRACTIONf_dihedral_angle_d11.323339
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0056-2.06460.32131220.23442327244982
2.0646-2.13120.29071420.24382699284196
2.1312-2.20740.30421340.23932786292098
2.2074-2.29580.2641260.23352786291298
2.2958-2.40030.30831370.2322791292898
2.4003-2.52680.28271450.23492758290398
2.5268-2.68510.26311460.23012832297899
2.6851-2.89230.25981570.222766292399
2.8923-3.18330.27091520.22522810296299
3.1833-3.64370.22971620.19052789295199
3.6437-4.58970.19441500.16172834298499
4.5897-41.09250.24091580.18842841299998

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