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- PDB-7ovj: Protein kinase MKK7 in complex with difluoro-phenethyltriazole-su... -

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Basic information

Entry
Database: PDB / ID: 7ovj
TitleProtein kinase MKK7 in complex with difluoro-phenethyltriazole-substituted pyrazolopyrimidine
ComponentsDual specificity mitogen-activated protein kinase kinase 7
KeywordsTRANSFERASE / Inhibitor / Complex / MKK7 / Kinase / Triazole / Click-Chemistry / CuACC
Function / homology
Function and homology information


JUN kinase kinase activity / regulation of motor neuron apoptotic process / mitogen-activated protein kinase kinase / response to osmotic stress / Fc-epsilon receptor signaling pathway / : / positive regulation of telomere capping / MAP kinase kinase activity / Uptake and function of anthrax toxins / cellular response to interleukin-1 ...JUN kinase kinase activity / regulation of motor neuron apoptotic process / mitogen-activated protein kinase kinase / response to osmotic stress / Fc-epsilon receptor signaling pathway / : / positive regulation of telomere capping / MAP kinase kinase activity / Uptake and function of anthrax toxins / cellular response to interleukin-1 / MAP kinase activity / response to tumor necrosis factor / response to UV / stress-activated MAPK cascade / positive regulation of JUN kinase activity / JNK cascade / positive regulation of telomere maintenance via telomerase / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / molecular function activator activity / FCERI mediated MAPK activation / positive regulation of JNK cascade / response to wounding / cellular senescence / response to heat / protein tyrosine kinase activity / cellular response to lipopolysaccharide / protein phosphatase binding / Oxidative Stress Induced Senescence / positive regulation of ERK1 and ERK2 cascade / protein serine kinase activity / apoptotic process / protein kinase binding / positive regulation of DNA-templated transcription / enzyme binding / magnesium ion binding / signal transduction / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / 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-24N / Dual specificity mitogen-activated protein kinase kinase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsWiese, J.N. / Buehrmann, M. / Mueller, M.P. / Rauh, D.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Optimization of Covalent MKK7 Inhibitors via Crude Nanomole-Scale Libraries.
Authors: Gehrtz, P. / Marom, S. / Buhrmann, M. / Hardick, J. / Kleinbolting, S. / Shraga, A. / Dubiella, C. / Gabizon, R. / Wiese, J.N. / Muller, M.P. / Cohen, G. / Babaev, I. / Shurrush, K. / Avram, ...Authors: Gehrtz, P. / Marom, S. / Buhrmann, M. / Hardick, J. / Kleinbolting, S. / Shraga, A. / Dubiella, C. / Gabizon, R. / Wiese, J.N. / Muller, M.P. / Cohen, G. / Babaev, I. / Shurrush, K. / Avram, L. / Resnick, E. / Barr, H. / Rauh, D. / London, N.
History
DepositionJun 15, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 20, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 10, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 17, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Sep 14, 2022Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.4Jan 31, 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: Dual specificity mitogen-activated protein kinase kinase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6562
Polymers36,1751
Non-polymers4821
Water1,38777
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13590 Å2
Unit cell
Length a, b, c (Å)61.050, 68.800, 83.220
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 Dual specificity mitogen-activated protein kinase kinase 7 / MAP kinase kinase 7 / MAPKK 7 / JNK-activating kinase 2 / MAPK/ERK kinase 7 / MEK 7 / Stress- ...MAP kinase kinase 7 / MAPKK 7 / JNK-activating kinase 2 / MAPK/ERK kinase 7 / MEK 7 / Stress-activated protein kinase kinase 4 / SAPK kinase 4 / SAPKK-4 / SAPKK4 / c-Jun N-terminal kinase kinase 2 / JNK kinase 2 / JNKK 2


Mass: 36174.941 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K7, JNKK2, MEK7, MKK7, PRKMK7, SKK4 / Production host: Escherichia coli (E. coli)
References: UniProt: O14733, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-24N / 1-[(3~{R})-3-[4-azanyl-3-[1-[2,2-bis(fluoranyl)-2-phenyl-ethyl]-1,2,3-triazol-4-yl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]propan-1-one


Mass: 481.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H25F2N9O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 77 / 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: 2.42 Å3/Da / Density % sol: 49.08 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 180-220 mM sodium citrate, 15-25 % PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9197 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Nov 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9197 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. obs: 15135 / % possible obs: 100 % / Redundancy: 13.22 % / Biso Wilson estimate: 54.62 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.0071 / Net I/σ(I): 23.3
Reflection shellResolution: 2.35→2.4 Å / Mean I/σ(I) obs: 3.21 / Num. unique obs: 894 / CC1/2: 0.88 / Rrim(I) all: 0.942

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
PHENIX1.19.1_4122refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6QFL

6qfl


Resolution: 2.35→45.66 Å / SU ML: 0.1547 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 25.5713
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2445 756 5 %
Rwork0.2017 14374 -
obs0.2038 15130 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.81 Å2
Refinement stepCycle: LAST / Resolution: 2.35→45.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2119 0 35 77 2231
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00142205
X-RAY DIFFRACTIONf_angle_d0.44822980
X-RAY DIFFRACTIONf_chiral_restr0.0404331
X-RAY DIFFRACTIONf_plane_restr0.0034377
X-RAY DIFFRACTIONf_dihedral_angle_d10.7926828
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.35-2.530.28181480.24032811X-RAY DIFFRACTION99.93
2.53-2.790.31091480.24412830X-RAY DIFFRACTION99.97
2.79-3.190.29681490.24022840X-RAY DIFFRACTION100
3.19-4.020.2441530.20242892X-RAY DIFFRACTION100
4.02-45.660.2141580.17893001X-RAY DIFFRACTION99.87
Refinement TLS params.Method: refined / Origin x: -18.4193257956 Å / Origin y: -9.97497331132 Å / Origin z: 12.3006263093 Å
111213212223313233
T0.473585631464 Å2-0.0435839223052 Å20.0183451613609 Å2-0.335909587491 Å2-0.0219026781358 Å2--0.370501183545 Å2
L1.90580514257 °2-1.13125717806 °20.651392813021 °2-1.17195132439 °2-0.601905772207 °2--1.09061718712 °2
S-0.0208939090799 Å °-0.128267611049 Å °0.0240589071557 Å °0.0937293709828 Å °0.0420107282115 Å °-0.00209188649406 Å °-0.112101061246 Å °-0.0371331875801 Å °-0.0274172042348 Å °
Refinement TLS groupSelection details: all

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