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Basic information

Entry
Database: PDB / ID: 8enj
TitleDesign, synthesis, biological evaluation, and X-ray crystallography of diarylpyrazole derivatives possessing terminal arylsulfonamide moieties as anti-proliferative agents targeting c-Jun N-terminal kinase (JNK)
ComponentsMitogen-activated protein kinase 10
KeywordsHYDROLASE / Cancer / JNK / Leukemia
Function / homology
Function and homology information


JUN kinase activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / MAP kinase kinase activity / response to light stimulus / mitogen-activated protein kinase / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / FCERI mediated MAPK activation / regulation of circadian rhythm ...JUN kinase activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / MAP kinase kinase activity / response to light stimulus / mitogen-activated protein kinase / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / FCERI mediated MAPK activation / regulation of circadian rhythm / cellular senescence / rhythmic process / Oxidative Stress Induced Senescence / protein phosphorylation / protein serine kinase activity / signal transduction / mitochondrion / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase, JNK / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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-WNK / Mitogen-activated protein kinase 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsPark, H. / Mersal, K.I.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea) Korea, Republic Of
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Evaluation of novel pyrazol-4-yl pyridine derivatives possessing arylsulfonamide tethers as c-Jun N-terminal kinase (JNK) inhibitors in leukemia cells.
Authors: Mersal, K.I. / Abdel-Maksoud, M.S. / Ali, E.M.H. / Ammar, U.M. / Zaraei, S.O. / Haque, M.M. / Das, T. / Hassan, N.F. / Kim, E.E. / Lee, J.S. / Park, H. / Lee, K.H. / El-Gamal, M.I. / Kim, H. ...Authors: Mersal, K.I. / Abdel-Maksoud, M.S. / Ali, E.M.H. / Ammar, U.M. / Zaraei, S.O. / Haque, M.M. / Das, T. / Hassan, N.F. / Kim, E.E. / Lee, J.S. / Park, H. / Lee, K.H. / El-Gamal, M.I. / Kim, H.K. / Ibrahim, T.M. / Oh, C.H.
History
DepositionSep 30, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,1712
Polymers52,6491
Non-polymers5221
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.670, 71.840, 107.230
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Mitogen-activated protein kinase 10 / MAPK 10 / MAP kinase p49 3F12 / Stress-activated protein kinase 1b / SAPK1b / Stress-activated ...MAPK 10 / MAP kinase p49 3F12 / Stress-activated protein kinase 1b / SAPK1b / Stress-activated protein kinase JNK3 / c-Jun N-terminal kinase 3


Mass: 52649.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK10, JNK3, JNK3A, PRKM10, SAPK1B / Production host: Escherichia coli (E. coli)
References: UniProt: P53779, mitogen-activated protein kinase
#2: Chemical ChemComp-WNK / N-[3-({(4P)-4-[(3M)-1-tert-butyl-3-(3-hydroxyphenyl)-1H-pyrazol-4-yl]pyridin-2-yl}amino)propyl]-4-hydroxybenzene-1-sulfonamide


Mass: 521.631 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H31N5O4S / Feature type: SUBJECT OF INVESTIGATION
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

Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 0.2 M ammonium tartrate pH 7.2, 18 % PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 2.81→71.84 Å / Num. obs: 10268 / % possible obs: 99.9 % / Redundancy: 6.6 % / Biso Wilson estimate: 48.71 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.118 / Net I/σ(I): 9.6
Reflection shellResolution: 2.81→2.96 Å / Num. unique obs: 1470 / CC1/2: 0.963

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Processing

Software
NameVersionClassification
PHENIXdev_4694refinement
MOSFLMdata reduction
pointlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1JNK

1jnk


Resolution: 2.81→59.68 Å / SU ML: 0.3931 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 34.1849
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2948 488 4.79 %
Rwork0.2361 9706 -
obs0.239 10194 99.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 63.43 Å2
Refinement stepCycle: LAST / Resolution: 2.81→59.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2682 0 37 0 2719
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00472782
X-RAY DIFFRACTIONf_angle_d0.54273769
X-RAY DIFFRACTIONf_chiral_restr0.0385414
X-RAY DIFFRACTIONf_plane_restr0.0035474
X-RAY DIFFRACTIONf_dihedral_angle_d20.04241036
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.81-3.220.39841600.31363158X-RAY DIFFRACTION99.22
3.22-4.050.3161690.23523194X-RAY DIFFRACTION99.79
4.05-59.680.24611590.21163354X-RAY DIFFRACTION99.94
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)
15.616539387670.2185102440160.3412948666884.477962768921.066888130797.46019735044-0.0449689976542-0.637009402843-0.1260786901721.104411196290.571797603133-0.2614391514880.03803756047721.08215374108-0.6861709709960.8209260964720.0521077771261-0.1105521948380.483417246055-0.07149900292130.40727104581225.813189325410.312287515445.9678615395
21.07763368612-1.226108987440.8923641901582.61100721099-0.1844602180242.37952777496-0.1534856149030.2510240825120.09578218564910.231238430289-0.148989254322-0.2986129931050.558866440747-0.05009316054870.2860292392150.636008546572-0.1301383450870.06057205776210.445723275903-0.01674320453020.33870929840116.058317310115.29751333737.7172780036
31.776591640410.9874390221021.73086985662.617567972280.1080328442674.344673624090.06667770252220.192137261027-0.0825673481320.158761863195-0.157374808452-0.1499770758650.3217650278780.03436707775780.04976370334880.471164017223-0.01507212307010.04066128518460.308400190673-0.01791177425120.30531221667915.812594814510.850528589127.248212767
41.804085725221.61524178055-0.9352776986186.59346992682.179864527922.292359035990.211893291446-0.09586969222950.117611556616-0.1606001169760.0337219180906-0.0190241824649-1.101542897180.2819556866120.03183917591490.690461458101-0.14378346832-0.01454155692410.376510095888-0.04582228873230.27687520967921.275822931525.812706245719.3178577623
53.061508922241.597708918270.7160529840224.275484087990.7093019175343.17678586687-0.1562790354160.3547935885160.197327057691-0.9012151674250.23637546989-0.234169441586-0.6581005248090.436954460633-0.1053316491040.684735035335-0.02406395931580.05447317782110.423231428849-0.06021479000620.4167533414820.512729869822.13701452485.36070111978
62.669894237543.805336706640.9295325971745.46159027561.245036252652.920920758460.143861399986-0.101276044955-0.501505203968-0.7872850631040.174265083808-0.5633257345960.2754056678730.284619372951-0.2969460244350.6238810921230.1306825888580.02854444323690.377232097278-0.02970174678250.43057694020415.41768819751.594754791972.67925820019
71.4485940287-0.3295814270411.917755032730.8102081212510.9395272317335.098546789980.0371797961057-0.2737130783230.1968789854130.108002639499-0.3732197974230.45715589261-0.732630052975-0.9427244793160.3070512025450.728095727772-0.08940067203280.09586837163590.451088579889-0.03088919729320.3779427364419.321506550418.721238054723.9413218101
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 45 through 75 )45 - 751 - 31
22chain 'A' and (resid 76 through 130 )76 - 13032 - 86
33chain 'A' and (resid 131 through 210 )131 - 21087 - 166
44chain 'A' and (resid 211 through 241 )211 - 241167 - 192
55chain 'A' and (resid 242 through 312 )242 - 312193 - 263
66chain 'A' and (resid 313 through 339 )313 - 339264 - 290
77chain 'A' and (resid 340 through 400 )340 - 400291 - 333

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