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- PDB-7ovl: Protein kinase MKK7 in complex with methoxycyclohexyl-substituted... -

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Basic information

Entry
Database: PDB / ID: 7ovl
TitleProtein kinase MKK7 in complex with methoxycyclohexyl-substituted indazole
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 / MAP kinase activity / 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 / MAP kinase activity / cellular response to interleukin-1 / response to tumor necrosis factor / stress-activated MAPK cascade / response to UV / positive regulation of JUN kinase activity / JNK cascade / positive regulation of telomerase activity / 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 phosphatase binding / protein tyrosine kinase activity / Oxidative Stress Induced Senescence / cellular response to lipopolysaccharide / positive regulation of ERK1 and ERK2 cascade / phosphorylation / protein serine kinase activity / apoptotic process / protein kinase binding / positive regulation of DNA-templated transcription / magnesium ion binding / enzyme 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-1XZ / Dual specificity mitogen-activated protein kinase kinase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsBuehrmann, M. / Wiese, J.N. / 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 17, 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 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

Downloads & links

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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)36,6482
Polymers36,1471
Non-polymers5021
Water543
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 area13550 Å2
Unit cell
Length a, b, c (Å)60.230, 67.680, 84.730
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 / MAPKK 7 / JNK-activating kinase 2 / MAPK/ERK kinase 7 / MEK 7 / Stress-activated protein kinase ...MAPKK 7 / JNK-activating kinase 2 / MAPK/ERK kinase 7 / MEK 7 / Stress-activated protein kinase kinase 4 / SAPKK4 / c-Jun N-terminal kinase kinase 2 / JNKK 2


Mass: 36146.859 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-1XZ / 3-(2~{H}-indazol-3-yl)-~{N}-[[1-[(1~{R},2~{R})-2-methoxycyclohexyl]-1,2,3-triazol-4-yl]methyl]-5-(propanoylamino)benzamide


Mass: 501.580 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H31N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 2.39 Å3/Da / Density % sol: 48.51 %
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: 2.9→50 Å / Num. obs: 8090 / % possible obs: 100 % / Redundancy: 12.99 % / Biso Wilson estimate: 91.18 Å2 / Rrim(I) all: 0.112 / Net I/σ(I): 15
Reflection shellResolution: 2.9→3 Å / Mean I/σ(I) obs: 1.57 / Num. unique obs: 766 / CC1/2: 0.76 / Rrim(I) all: 1.511

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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: 2.9→49.09 Å / SU ML: 0.4832 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 36.4197
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2703 405 5.01 %
Rwork0.2471 7678 -
obs0.2483 8083 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 99.68 Å2
Refinement stepCycle: LAST / Resolution: 2.9→49.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2134 0 37 3 2174
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00182248
X-RAY DIFFRACTIONf_angle_d0.52043046
X-RAY DIFFRACTIONf_chiral_restr0.0391338
X-RAY DIFFRACTIONf_plane_restr0.0035392
X-RAY DIFFRACTIONf_dihedral_angle_d11.9878830
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-3.320.38711310.36632489X-RAY DIFFRACTION99.85
3.32-4.180.29911340.26662533X-RAY DIFFRACTION99.81
4.18-49.090.23761400.21732656X-RAY DIFFRACTION99.96
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)
18.376970687472.33236187236-2.132018006974.846917260341.59457038846.737181031550.2739414324570.3846100354460.202889926235-0.1558007545830.1962168964720.516047706974-0.0372578630692-0.508335120172-0.5039462958740.7356892285810.0836934045903-0.05152469796630.7991655201980.02134348326850.698993305173-32.2765594273-0.4212149443314.21615849055
28.62406041958-4.819969032621.272435085412.66851633311-1.273252128743.90294335574-0.272149862236-0.4873313822980.2105268395090.07366508583820.24106785586-0.0671500759986-0.05258133991070.0122808552870.030364616490.553620157073-0.1363551782340.04597565842890.727872025665-0.07419824800640.571348345632-19.2544595802-6.9801162738411.5114845995
34.219161433860.9324672524210.3067329425254.79611300652-0.7519889005892.7222176128-0.0512253926168-0.6041506306840.05453569605150.4847230489110.0523092032581-0.2319273589940.01651358292720.2869338538980.04030588746090.551218888977-0.00410976731607-0.02145701167990.966222819441-0.1198542809550.571270964833-9.42655296234-17.191045654419.4858757386
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 118 through 189 )118 - 1891 - 67
22chain 'A' and (resid 190 through 300 )190 - 30068 - 166
33chain 'A' and (resid 301 through 418 )301 - 418167 - 279

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