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- PDB-3dy7: X-ray structure of the human mitogen-activated protein kinase kin... -

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Basic information

Entry
Database: PDB / ID: 3dy7
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 / dual specificity protein kinase / non-ATP-competitive kinase inhibitor / inhibitor-bound protein kinase / ATP-bound protein kinase / Acetylation / ATP-binding / Disease mutation / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase / Tyrosine-protein kinase
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / 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 / positive regulation of endodermal cell differentiation / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / 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 / 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 / central nervous system neuron differentiation / 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 / face development / endodermal cell differentiation / MAP kinase kinase activity / Bergmann glial cell differentiation / positive regulation of ATP biosynthetic process / thyroid gland development / Uptake and function of anthrax toxins / positive regulation of protein serine/threonine kinase activity / protein kinase activator activity / response to axon injury / Schwann cell development / keratinocyte differentiation / 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 / MAP3K8 (TPL2)-dependent MAPK1/3 activation / 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 / neuron differentiation / chemotaxis / 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 / late endosome / MAPK cascade / heart development / response to oxidative stress / protein tyrosine kinase activity / scaffold protein binding / cell cortex / perikaryon / 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 / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / 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
Chem-1CX / ADENOSINE-5'-TRIPHOSPHATE / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.7 Å
AuthorsOhren, J.F. / Pavlovsky, A. / Zhang, E.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Beyond the MEK-pocket: can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK?
Authors: Tecle, H. / Shao, J. / Li, Y. / Kothe, M. / Kazmirski, S. / Penzotti, J. / Ding, Y.H. / Ohren, J. / Moshinsky, D. / Coli, R. / Jhawar, N. / Bora, E. / Jacques-O'Hagan, S. / Wu, J.
#1: Journal: 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
DepositionJul 25, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 16, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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 / _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.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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,9144
Polymers37,9311
Non-polymers9843
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.754, 81.754, 128.893
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number171
Space group name H-MP62

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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 / Fragment: Protein Kinase Domain, UNP residues 62-393
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Plasmid: pET24b / Production host: Escherichia coli (E. coli) / Strain (production host): Bl21(de3)
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#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-1CX / (5S)-4,5-difluoro-6-[(2-fluoro-4-iodophenyl)imino]-N-(2-hydroxyethoxy)cyclohexa-1,3-diene-1-carboxamide


Mass: 452.167 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12F3IN2O3

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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: 3.28 Å3/Da / Density % sol: 62.48 %
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: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 28, 2001 / Details: single crystal
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→30 Å / Num. all: 12527 / Num. obs: 12527 / % possible obs: 93.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.97 % / Biso Wilson estimate: 80.8 Å2 / Rmerge(I) obs: 0.052 / Rsym value: 0.052
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.413 / Mean I/σ(I) obs: 6 / Num. unique all: 1260 / Rsym value: 0.413 / % possible all: 95.6

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Processing

Software
NameVersionClassification
REFMAC5.4.0069refinement
ADSCQuantumdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1S9J

1s9j


Resolution: 2.7→30 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.912 / SU B: 12.27 / SU ML: 0.251 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.531 / ESU R Free: 0.316 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26898 632 5 %RANDOM
Rwork0.24728 ---
obs0.24834 11895 93.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 69.209 Å2
Baniso -1Baniso -2Baniso -3
1-2.59 Å21.3 Å20 Å2
2--2.59 Å20 Å2
3----3.89 Å2
Refinement stepCycle: LAST / Resolution: 2.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2037 0 56 0 2093
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222123
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.292.012872
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3985258
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.71124.0786
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.37715369
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8281512
X-RAY DIFFRACTIONr_chiral_restr0.0790.2315
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211567
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5631.51297
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.06322092
X-RAY DIFFRACTIONr_scbond_it1.2643826
X-RAY DIFFRACTIONr_scangle_it2.2584.5780
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.771 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 41 -
Rwork0.363 865 -
obs--91.79 %

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