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- PDB-7ovk: Protein kinase MKK7 in complex with 5-bromo-2-hydroxyphenyl-subst... -

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Basic information

Entry
Database: PDB / ID: 7ovk
TitleProtein kinase MKK7 in complex with 5-bromo-2-hydroxyphenyl-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 maintenance / MAP kinase kinase activity / response to tumor necrosis factor / Uptake and function of anthrax toxins / MAP kinase activity ...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 maintenance / MAP kinase kinase activity / response to tumor necrosis factor / Uptake and function of anthrax toxins / MAP kinase activity / cellular response to interleukin-1 / stress-activated MAPK cascade / response to UV / JNK cascade / molecular function activator activity / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of JNK cascade / FCERI mediated MAPK activation / response to wounding / cellular senescence / cellular response to lipopolysaccharide / response to heat / protein tyrosine kinase activity / 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 / cytoplasm / cytosol
Similarity search - Function
: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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. ...: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-2I5 / Dual specificity mitogen-activated protein kinase kinase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsKleinboelting, S. / 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
Revision 1.4Oct 12, 2022Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 2.0May 24, 2023Group: Non-polymer description / Category: chem_comp / Item: _chem_comp.formula
Revision 2.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)36,7513
Polymers36,1471
Non-polymers6042
Water72140
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint-1 kcal/mol
Surface area13370 Å2
Unit cell
Length a, b, c (Å)61.080, 68.090, 85.080
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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-2I5 / 1-[(3~{R})-3-[4-azanyl-3-[1-(5-bromanyl-2-oxidanyl-phenyl)-1,2,3-triazol-4-yl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]propan-1-one


Mass: 512.362 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22BrN9O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.45 Å3/Da / Density % sol: 49.74 %
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: 0.9999 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 31, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 22885 / % possible obs: 100 % / Redundancy: 13.37 % / Biso Wilson estimate: 53.56 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.069 / Net I/σ(I): 19.69
Reflection shellResolution: 2.05→2.15 Å / Mean I/σ(I) obs: 2.23 / Num. unique obs: 2987 / CC1/2: 0.8 / Rrim(I) all: 1.281

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PHENIX1.19.2_4158refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6QFL

6qfl


Resolution: 2.05→45.47 Å / SU ML: 0.282 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 27.7378
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2444 1145 5 %
Rwork0.2152 21738 -
obs0.2167 22883 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60.43 Å2
Refinement stepCycle: LAST / Resolution: 2.05→45.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2012 0 39 40 2091
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022092
X-RAY DIFFRACTIONf_angle_d0.42162819
X-RAY DIFFRACTIONf_chiral_restr0.0397311
X-RAY DIFFRACTIONf_plane_restr0.0034352
X-RAY DIFFRACTIONf_dihedral_angle_d12.3501773
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.140.3381400.31982661X-RAY DIFFRACTION100
2.14-2.260.29011410.25942670X-RAY DIFFRACTION100
2.26-2.40.2581410.2582675X-RAY DIFFRACTION100
2.4-2.580.30051410.26752685X-RAY DIFFRACTION100
2.58-2.840.30091430.262723X-RAY DIFFRACTION100
2.84-3.250.31621430.26662705X-RAY DIFFRACTION100
3.25-4.10.21191440.20692750X-RAY DIFFRACTION100
4.1-45.470.21591520.17632869X-RAY DIFFRACTION99.87
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)
13.14591603212-0.003966549411650.7030239055211.28241176618-1.357677462733.22125765456-0.09077038852880.0345503869178-0.4625189408120.05608535621020.28439412538-0.2449798700640.4109640151820.154126032462-0.0001255132953050.5829928851320.04155716264250.007070735271220.494213903581-0.001240622437960.51792044564992.5941760675-2.28530172553-1.43923616451
23.91285490017-1.008150606-0.9177598316051.599189162-0.442185585331.640511760950.0436813040562-0.623910089819-0.08155687066510.296530227619-0.06847963134070.05949910514-0.03332394915540.231859018005-7.31390545169E-50.5212589293660.00581498384922-0.02111041443930.4747178968480.0291525210520.45204404575893.11499444961.1780012001910.8691331803
32.36534434832-1.14683889134-0.7902755237161.03017675360.5723415155621.53139162053-0.0952172444434-0.0951504484387-0.00138568980686-0.08603088560850.0511901053085-0.1456280362670.1354120214460.2921344549590.0001193258953590.446364079027-0.00131075599355-0.02207802330540.469187297460.04176108445980.48889467119774.167973145410.023581343110.771119256
43.05956577945-0.969974737928-1.121023213222.86464998558-1.189915999511.3278479736-0.226871844834-0.466437095618-0.371923143250.1678142718680.248587942557-0.2459053118210.3252076639440.416855045737-0.0001401099008440.5073883319040.03088762681590.01527700082880.5143809884730.0303498972230.55104041818179.43677787458.0773013468111.7411258696
50.5300982156430.5001135757940.318392819661.342510566851.598320120732.03257958169-0.203494278397-0.001533632971370.2418325719860.1133834660380.250595729301-0.122207653209-0.34131228970.3340045260230.0002008339157570.48907563988-0.0136216921049-0.05254709041870.551343194121-0.007974704383570.5137996276676.774555131224.817373487920.1592978827
62.991957562790.211952956586-0.3413808282493.515835357091.708602408173.033199777130.0628158025339-0.5759194866160.00507356563070.8480089532290.0803334852940.132561581670.0962445775585-0.126806842526-5.80648370843E-50.4821613808710.007851348244850.03258060012780.554790142180.01210079599670.4424993672165.808648919416.622919400223.7456414785
72.00563342514-0.7949948079720.8090794241022.20853886161.679650454072.42315631579-0.004324346234690.569277786221-0.501427099736-0.379261536027-0.1798625932270.1593849353480.245541217152-0.467290078867-0.00080798107430.512231448239-0.0383499934293-0.01742086757430.522102962333-0.01795632325210.60327834804766.09349847239.371808489564.70710006098
Refinement TLS group

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

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11(chain A and resseq 118:160)118 - 1601 - 39
22(chain A and resseq 161:212)161 - 21240 - 91
33(chain A and resseq 213:253)213 - 25392 - 132
44(chain A and resseq 254:318)254 - 318133 - 157
55(chain A and resseq 319:353)319 - 353158 - 192
66(chain A and resseq 354:393)354 - 393193 - 232
77(chain A and resseq 394:418)394 - 418233 - 256

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