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- PDB-3fme: Crystal Structure of Human Mitogen-Activated Protein Kinase Kinas... -

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Basic information

Entry
Database: PDB / ID: 3fme
TitleCrystal Structure of Human Mitogen-Activated Protein Kinase Kinase 6 (MEK6) Activated Mutant (S207D, T211D)
ComponentsDual specificity mitogen-activated protein kinase kinase 6
KeywordsTRANSFERASE / kinase / active mutant / structural genomics consortium / SCG / SGC / ATP-binding / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase / Tyrosine-protein kinase
Function / homology
Function and homology information


cellular response to sorbitol / ovulation cycle process / : / positive regulation of prostaglandin secretion / mitogen-activated protein kinase kinase / negative regulation of cold-induced thermogenesis / stress-activated protein kinase signaling cascade / Myogenesis / PI5P Regulates TP53 Acetylation / positive regulation of nitric-oxide synthase biosynthetic process ...cellular response to sorbitol / ovulation cycle process / : / positive regulation of prostaglandin secretion / mitogen-activated protein kinase kinase / negative regulation of cold-induced thermogenesis / stress-activated protein kinase signaling cascade / Myogenesis / PI5P Regulates TP53 Acetylation / positive regulation of nitric-oxide synthase biosynthetic process / p38MAPK cascade / MAP kinase kinase activity / Uptake and function of anthrax toxins / stress-activated MAPK cascade / signal transduction in response to DNA damage / cardiac muscle contraction / regulation of signal transduction by p53 class mediator / activated TAK1 mediates p38 MAPK activation / response to ischemia / NOD1/2 Signaling Pathway / PKR-mediated signaling / bone development / osteoblast differentiation / Interleukin-1 signaling / MAPK cascade / cellular senescence / protein tyrosine kinase activity / Oxidative Stress Induced Senescence / positive regulation of MAPK cascade / cytoskeleton / regulation of cell cycle / response to xenobiotic stimulus / positive regulation of protein phosphorylation / positive regulation of apoptotic process / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / protein kinase binding / signal transduction / nucleoplasm / ATP binding / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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, ATP binding site / Protein kinases ATP-binding region signature. ...Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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, ATP binding site / Protein kinases ATP-binding region signature. / 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
STAUROSPORINE / Dual specificity mitogen-activated protein kinase kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.26 Å
AuthorsFilippakopoulos, P. / Barr, A. / Pike, A.C.W. / Berridge, G. / Elkins, J. / Fedorov, O. / Keates, T. / Savitsky, P. / Soundararajan, M. / von Delft, F. ...Filippakopoulos, P. / Barr, A. / Pike, A.C.W. / Berridge, G. / Elkins, J. / Fedorov, O. / Keates, T. / Savitsky, P. / Soundararajan, M. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Weigelt, J. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: To be Published
Title: Crystal Structure of Human Mitogen-Activated Protein Kinase Kinase 6 (MEK6) Activated Mutant (S207D, T211D)
Authors: Filippakopoulos, P. / Barr, A. / Pike, A.C.W. / Berridge, G. / Elkins, J. / Fedorov, O. / Keates, T. / Savitsky, P. / Soundararajan, M. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / ...Authors: Filippakopoulos, P. / Barr, A. / Pike, A.C.W. / Berridge, G. / Elkins, J. / Fedorov, O. / Keates, T. / Savitsky, P. / Soundararajan, M. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Weigelt, J. / Bountra, C. / Knapp, S.
History
DepositionDec 21, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 6, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Oct 25, 2017Group: Author supporting evidence / Category: pdbx_struct_assembly_auth_evidence
Revision 1.3Jan 31, 2018Group: Database references / Structure summary / Category: audit_author / citation_author / Item: _audit_author.name / _citation_author.name
Revision 1.4Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Sep 6, 2023Group: 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 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,2162
Polymers32,7501
Non-polymers4671
Water84747
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)132.756, 132.756, 45.719
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Detailsanalytical ultracentrifugation (AUC) velocity experiments show that the protein is dimeric in solution.

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Components

#1: Protein Dual specificity mitogen-activated protein kinase kinase 6 / MAP kinase kinase 6 / MAPKK 6 / MAPK/ERK kinase 6 / SAPKK3


Mass: 32749.885 Da / Num. of mol.: 1 / Fragment: UNP residues 47-334, Protein kinase domain / Mutation: S207D, T211D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K6, MEK6, MKK6, PRKMK6 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3
References: UniProt: P52564, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-STU / STAUROSPORINE / Staurosporine


Mass: 466.531 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H26N4O3 / Comment: anticancer, antifungal, antibiotic, alkaloid*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 47 / Source method: isolated from a natural source / Formula: H2O

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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: 3.55 Å3/Da / Density % sol: 65.36 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.9
Details: 0.05M Mg(COO)2 10w/v PEG_3350, pH 5.9, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 7, 2008
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.26→38.32 Å / Num. all: 21933 / Num. obs: 21933 / % possible obs: 100 % / Redundancy: 9.2 % / Biso Wilson estimate: 52.7 Å2 / Rmerge(I) obs: 0.082 / Rsym value: 0.082 / Net I/σ(I): 14.2
Reflection shellResolution: 2.26→2.38 Å / Redundancy: 8.3 % / Rmerge(I) obs: 0.812 / Mean I/σ(I) obs: 2.8 / Num. unique all: 3180 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 53.96 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å37.66 Å
Translation2.5 Å37.66 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.2data scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.006data extraction
CrystalCleardata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRIES 2DYL, 3EQB, 1S9J

2dyl

3eqb

1s9j


Resolution: 2.26→38 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.945 / WRfactor Rfree: 0.287 / WRfactor Rwork: 0.282 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.845 / SU B: 11.741 / SU ML: 0.15 / SU R Cruickshank DPI: 0.245 / SU Rfree: 0.198 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.2 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.236 1096 5 %RANDOM
Rwork0.212 ---
all0.213 21918 --
obs0.213 21907 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 87.24 Å2 / Biso mean: 43.869 Å2 / Biso min: 7.22 Å2
Baniso -1Baniso -2Baniso -3
1-1.69 Å20.84 Å20 Å2
2--1.69 Å20 Å2
3----2.53 Å2
Refinement stepCycle: LAST / Resolution: 2.26→38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2015 0 35 47 2097
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222097
X-RAY DIFFRACTIONr_bond_other_d0.0010.021392
X-RAY DIFFRACTIONr_angle_refined_deg1.3082.0042853
X-RAY DIFFRACTIONr_angle_other_deg0.8883.0023406
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2165264
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.32724.875
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.10915347
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.726157
X-RAY DIFFRACTIONr_chiral_restr0.0740.2328
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212283
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02379
X-RAY DIFFRACTIONr_mcbond_it2.12631338
X-RAY DIFFRACTIONr_mcbond_other0.5613533
X-RAY DIFFRACTIONr_mcangle_it3.5752144
X-RAY DIFFRACTIONr_scbond_it5.7667759
X-RAY DIFFRACTIONr_scangle_it7.87711709
LS refinement shellResolution: 2.26→2.319 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.314 60 -
Rwork0.244 1524 -
all-1584 -
obs--99.75 %
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)
18.0897-0.6923-5.3772.7103-0.7698.7076-0.2727-0.9737-1.46660.00090.39440.22451.0788-1.1124-0.12180.4022-0.17030.08930.86010.21820.83723.99548.33415.753
24.4149-0.2041.41053.24060.89275.3666-0.1338-0.1180.03840.0905-0.09280.4921-0.3908-0.45640.22660.0480.2231-0.02580.12880.0022-0.084621.22266.3696.232
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A46 - 128
2X-RAY DIFFRACTION2A129 - 333

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