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- PDB-1s9j: X-ray structure of the human mitogen-activated protein kinase kin... -

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Basic information

Entry
Database: PDB / ID: 1s9j
TitleX-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a complex with ligand and MgATP
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE / PROTEIN KINASE-LIGAND-MgATP COMPLEX / PROTEIN-PROTEIN INTERACTIONS
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / positive regulation of endodermal cell differentiation / regulation of vascular associated smooth muscle contraction / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development / MAP-kinase scaffold activity / positive regulation of muscle contraction ...epithelial cell proliferation involved in lung morphogenesis / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / positive regulation of endodermal cell differentiation / regulation of vascular associated smooth muscle contraction / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development / MAP-kinase scaffold activity / positive regulation of muscle contraction / labyrinthine layer development / regulation of axon regeneration / cerebellar cortex formation / melanosome transport / type B pancreatic cell proliferation / central nervous system neuron differentiation / Signaling by MAP2K mutants / vesicle transport along microtubule / positive regulation of axonogenesis / positive regulation of Ras protein signal transduction / regulation of Golgi inheritance / mitogen-activated protein kinase kinase kinase binding / triglyceride homeostasis / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / Frs2-mediated activation / MAPK3 (ERK1) activation / ERBB2-ERBB3 signaling pathway / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / endodermal cell differentiation / face development / MAP kinase kinase activity / positive regulation of ATP biosynthetic process / Bergmann glial cell differentiation / Uptake and function of anthrax toxins / thyroid gland development / protein kinase activator activity / positive regulation of protein serine/threonine kinase activity / response to axon injury / Schwann cell development / keratinocyte differentiation / MAP3K8 (TPL2)-dependent MAPK1/3 activation / neuron projection morphogenesis / ERK1 and ERK2 cascade / myelination / positive regulation of autophagy / protein serine/threonine/tyrosine kinase activity / dendrite cytoplasm / insulin-like growth factor receptor signaling pathway / response to glucocorticoid / thymus development / protein serine/threonine kinase activator activity / Signal transduction by L1 / cell motility / positive regulation of transcription elongation by RNA polymerase II / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / small GTPase binding / chemotaxis / neuron differentiation / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by BRAF and RAF1 fusions / cellular senescence / MAPK cascade / late endosome / heart development / scaffold protein binding / protein tyrosine kinase activity / cell cortex / perikaryon / response to oxidative stress / microtubule / early endosome / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / postsynaptic density / ciliary basal body / positive regulation of cell migration / axon / negative regulation of cell population proliferation / negative regulation of gene expression / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / centrosome / positive regulation of gene expression / protein-containing complex binding / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / glutamatergic synapse / endoplasmic reticulum / Golgi apparatus / signal transduction
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, ATP binding site ...: / 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, 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
ADENOSINE-5'-TRIPHOSPHATE / Chem-BBM / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Iodine-SAD / Resolution: 2.4 Å
AuthorsOhren, J.F. / Chen, H. / Pavlovsky, A. / Whitehead, C. / Yan, C. / McConnell, P. / Delaney, A. / Dudley, D.T. / Sebolt-Leopold, J. / Hasemann, C.A.
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2004
Title: Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition.
Authors: Ohren, J.F. / Chen, H. / Pavlovsky, A. / Whitehead, C. / Zhang, E. / Kuffa, P. / Yan, C. / McConnell, P. / Spessard, C. / Banotai, C. / Mueller, W.T. / Delaney, A. / Omer, C. / Sebolt- ...Authors: Ohren, J.F. / Chen, H. / Pavlovsky, A. / Whitehead, C. / Zhang, E. / Kuffa, P. / Yan, C. / McConnell, P. / Spessard, C. / Banotai, C. / Mueller, W.T. / Delaney, A. / Omer, C. / Sebolt-Leopold, J. / Dudley, D.T. / Leung, I.K. / Flamme, C. / Warmus, J. / Kaufman, M. / Barrett, S. / Tecle, H. / Hasemann, C.A.
History
DepositionFeb 4, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.3Feb 14, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model
Remark 300biomolecule Although the amino terminally truncated MEK1 is a monomer in solution and in the ...biomolecule Although the amino terminally truncated MEK1 is a monomer in solution and in the asymmetric unit, a potentially relevant homodimer can be generated as described in remark 350.

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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 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0234
Polymers37,9311
Non-polymers1,0933
Water1,964109
1
A: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules

A: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,0468
Polymers75,8612
Non-polymers2,1856
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_665-x+1,-y+1,z1
Unit cell
Length a, b, c (Å)81.591, 81.591, 129.213
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number171
Space group name H-MP62
DetailsAlthough the NH2-terminally truncated MEK1 is a monomer in solution and in the asu, a potentially relevant homodimer can be generated by the two-fold axis: -x+1, -y+1, z.

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Components

#1: Protein Dual specificity mitogen-activated protein kinase kinase 1 / MAP kinase kinase 1 / MAPKK 1 / ERK activator kinase 1 / MAPK/ERK kinase 1 / MEK1


Mass: 37930.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MEK1 / Plasmid: pET24b / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q02750, EC: 2.7.1.37
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#4: Chemical ChemComp-BBM / 5-BROMO-N-(2,3-DIHYDROXYPROPOXY)-3,4-DIFLUORO-2-[(2-FLUORO-4-IODOPHENYL)AMINO]BENZAMIDE


Mass: 561.089 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13BrF3IN2O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 109 / 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: 3.27 Å3/Da / Density % sol: 62.42 %
Crystal growTemperature: 288 K / Method: vapor diffusion, hanging drop / pH: 5
Details: PEG8K, Ammonium phosphate, Imidazole-malate, DTT, pH 5, VAPOR DIFFUSION, HANGING DROP, temperature 288K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: May 31, 2001
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→48 Å / Num. all: 18590 / Num. obs: 18389 / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.5 % / Rmerge(I) obs: 0.052 / Net I/σ(I): 31
Reflection shellResolution: 2.4→2.46 Å / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 1.8 / % possible all: 0.74

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
HKL-2000data reduction
CCP4(TRUNCATE)data scaling
CNXphasing
RefinementMethod to determine structure: Iodine-SAD
Starting model: Iodine substructure

Resolution: 2.4→47.7 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.916 / SU B: 9.282 / SU ML: 0.206 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.34 / ESU R Free: 0.249 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26933 923 5 %RANDOM
Rwork0.24458 ---
obs0.24577 17466 96.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 20.815 Å2
Baniso -1Baniso -2Baniso -3
1-1.92 Å20.96 Å20 Å2
2--1.92 Å20 Å2
3----2.88 Å2
Refinement stepCycle: LAST / Resolution: 2.4→47.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2261 0 59 109 2429
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0222384
X-RAY DIFFRACTIONr_bond_other_d0.0010.022176
X-RAY DIFFRACTIONr_angle_refined_deg0.9662.0043224
X-RAY DIFFRACTIONr_angle_other_deg0.71535090
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9815290
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0540.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.022581
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02447
X-RAY DIFFRACTIONr_nbd_refined0.1610.2474
X-RAY DIFFRACTIONr_nbd_other0.1860.22432
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.080.21349
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1050.267
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.0530.21
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.140.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1760.242
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0980.24
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_mcbond_it0.4681.51454
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.86222347
X-RAY DIFFRACTIONr_scbond_it0.9973930
X-RAY DIFFRACTIONr_scangle_it1.8234.5877
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.404 48
Rwork0.366 972
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)
1-0.07340.31920.07751.267-0.32871.9836-0.0094-0.09440.05450.05810.00690.06180.1014-0.21010.00250.1239-0.0042-0.04130.2238-0.04260.136932.027226.963649.9286
20.51420.0672-0.04940.56-0.32870.8840.02110.03190.0608-0.0041-0.0099-0.1290.06490.005-0.01120.1192-0.00130.01850.2032-0.02240.208237.899733.787131.6488
34.14283.4193-1.0106-2.5482-1.90241.3037-0.21320.02410.5188-0.22590.2016-0.1984-0.4804-0.18280.01170.3309-0.0339-0.04470.26680.06040.395537.029955.543619.4087
41.77670.09450.53670.8377-0.07871.44120.01480.17150.187-0.2521-0.0245-0.2108-0.11290.1660.00970.0692-0.00450.08750.14960.03170.185742.728539.145223.7681
5-62.3694-43.7259-89.956876.776622.1183-40.6271-1.51950.21290.3324-2.039-1.11114.0476-1.0271-1.3622.63060.1098-0.0629-0.11160.2016-0.00840.145131.26928.223440.2101
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA61 - 1461 - 86
2X-RAY DIFFRACTION2AA147 - 26487 - 204
3X-RAY DIFFRACTION3AA265 - 275205 - 215
4X-RAY DIFFRACTION4AA306 - 382246 - 322
5X-RAY DIFFRACTION5AD10011

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