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- PDB-7ovi: Protein kinase MKK7 in complex with phenethyltriazole-substituted... -

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Basic information

Entry
Database: PDB / ID: 7ovi
TitleProtein kinase MKK7 in complex with 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 maintenance / response to tumor necrosis factor / MAP kinase kinase activity / 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 / response to tumor necrosis factor / MAP kinase kinase activity / 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-2GI / Dual specificity mitogen-activated protein kinase kinase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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 1.4Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Nov 20, 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)36,5922
Polymers36,1471
Non-polymers4461
Water1,49583
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 area13740 Å2
Unit cell
Length a, b, c (Å)61.720, 68.490, 83.990
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-2GI / 1-[(3~{R})-3-[4-azanyl-3-[1-(2-phenylethyl)-1,2,3-triazol-4-yl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]propan-1-one


Mass: 445.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27N9O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 2.46 Å3/Da / Density % sol: 49.91 %
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: 1.95→50 Å / Num. obs: 26469 / % possible obs: 99.5 % / Redundancy: 13 % / Biso Wilson estimate: 51.05 Å2 / Rrim(I) all: 0.052 / Net I/σ(I): 23.53
Reflection shellResolution: 1.95→2.05 Å / Mean I/σ(I) obs: 1.55 / Num. unique obs: 3647 / Rrim(I) all: 1.573

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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: 1.95→49.74 Å / SU ML: 0.311 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 27.2513
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2504 1323 5 %
Rwork0.2092 25138 -
obs0.2112 26461 99.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 58.2 Å2
Refinement stepCycle: LAST / Resolution: 1.95→49.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2062 0 33 83 2178
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00922138
X-RAY DIFFRACTIONf_angle_d0.94482880
X-RAY DIFFRACTIONf_chiral_restr0.067316
X-RAY DIFFRACTIONf_plane_restr0.0077363
X-RAY DIFFRACTIONf_dihedral_angle_d14.1694793
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-2.030.38671440.38462728X-RAY DIFFRACTION99.9
2.03-2.120.34081460.27422775X-RAY DIFFRACTION100
2.12-2.230.26661450.23942759X-RAY DIFFRACTION99.9
2.23-2.370.32211410.27942677X-RAY DIFFRACTION96.05
2.37-2.560.27041470.25892783X-RAY DIFFRACTION100
2.56-2.810.24691470.24062795X-RAY DIFFRACTION100
2.81-3.220.2961470.24372803X-RAY DIFFRACTION100
3.22-4.050.26021500.19862847X-RAY DIFFRACTION99.93
4.06-49.740.20971560.17132971X-RAY DIFFRACTION99.81
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)
12.96550795765-0.636759147311-1.219692165364.459494239831.218187194557.97483184901-0.12184246008-0.230389019996-0.1116077866050.4017203752920.09238845922560.3031628517280.351249347121-0.04029777039930.0375504931670.2844107928690.001490286557240.003906727473140.3640661909630.02457333868530.43915347135466.854466581614.045209252916.1269972443
27.996642001253.15122363012.312939954194.59603987017-0.4548987203548.773100832310.03817854849220.0779934769436-0.3229954548430.05748034336840.00626645834769-0.2023508202480.5101311497930.154989310498-0.02240404871940.3684513655340.07736227416570.04729866919370.301290081477-0.0126506677550.29192336593494.744839252-0.319748096210.75058599861
36.03757067507-2.71138340487-0.7181271790231.96613849527-0.02209879289651.23056257558-0.224942954865-0.632417920976-0.1695963311670.2349695019790.2053989267420.08714311007230.1979642446170.1684047637030.04128995526960.4738230161670.00442152762176-0.009184861537970.371978466508-0.01266983138720.37758226081682.63162805165.7245026446111.5113230142
43.027602048393.074721352542.22132853953.359298554954.471786339578.57143998241-0.309191224136-0.2063605045260.1121878237830.01857850269980.25841645144-0.379952075811-0.2531845826540.4014050244090.1237279303030.3726250900760.00730196410402-0.01114405241990.4359321106530.01429170164480.42117732924178.726497395722.561790429219.4493840503
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 354 through 418 )354 - 418198 - 262
22chain 'A' and (resid 118 through 172 )118 - 1721 - 53
33chain 'A' and (resid 173 through 275 )173 - 27554 - 156
44chain 'A' and (resid 276 through 353 )276 - 353157 - 197

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