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- PDB-3zm4: Crystal structure of MEK1 in complex with fragment 1 -

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Basic information

Entry
Database: PDB / ID: 3zm4
TitleCrystal structure of MEK1 in complex with fragment 1
ComponentsDUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1
KeywordsTRANSFERASE
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
Chem-22T / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.37 Å
AuthorsAmaning, K. / Lowinsky, M. / Vallee, F. / Steier, V. / Marcireau, C. / Ugolini, A. / Delorme, C. / McCort, G. / Andouche, C. / Vougier, S. ...Amaning, K. / Lowinsky, M. / Vallee, F. / Steier, V. / Marcireau, C. / Ugolini, A. / Delorme, C. / McCort, G. / Andouche, C. / Vougier, S. / Llopart, S. / Halland, N. / Rak, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: The Use of Virtual Screening and Differential Scanning Fluorimetry for the Rapid Identification of Fragments Active Against Mek1.
Authors: Amaning, K. / Lowinski, M. / Vallee, F. / Steier, V. / Marcireau, C. / Ugolini, A. / Delorme, C. / Foucalt, F. / Mccort, G. / Derimay, N. / Andouche, C. / Vougier, S. / Llopart, S. / Halland, N. / Rak, A.
History
DepositionFeb 5, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 22, 2013Provider: repository / Type: Initial release
Revision 1.1May 29, 2013Group: Database references
Revision 1.2May 2, 2018Group: Data collection / Experimental preparation / Category: diffrn_source / exptl_crystal_grow
Item: _diffrn_source.pdbx_synchrotron_beamline / _exptl_crystal_grow.pdbx_details
Revision 1.3Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.4May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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)39,1822
Polymers38,9171
Non-polymers2651
Water2,468137
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)77.805, 77.805, 222.926
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-2020-

HOH

21A-2035-

HOH

31A-2066-

HOH

41A-2120-

HOH

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Components

#1: Protein DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1 / MAP KINASE KINASE 1 / MAPKK 1 / MKK1 / ERK ACTIVATOR KINASE 1 / MAPK/ERK KINASE 1 / MEK 1


Mass: 38916.879 Da / Num. of mol.: 1 / Fragment: RESIDUES 37-383 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-22T / 7-chloranyl-6-[(3S)-pyrrolidin-3-yl]oxy-2H-isoquinolin-1-one


Mass: 264.708 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H13ClN2O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 137 / 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: 2.5 Å3/Da / Density % sol: 50.85 % / Description: NONE
Crystal growpH: 7.7
Details: Appropriate single crystals were grown using this set-up in PEG 4000 18%, Tris 100mM pH7.7, DMSO 2% and CaCl2 0.2M and were extracted from the low volume drops, cryo-protected in mother ...Details: Appropriate single crystals were grown using this set-up in PEG 4000 18%, Tris 100mM pH7.7, DMSO 2% and CaCl2 0.2M and were extracted from the low volume drops, cryo-protected in mother liquor with 20% glycerol and flash cooled for synchrotron collection

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Type: ESRF / Wavelength: 0.9784
DetectorDate: Apr 27, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9784 Å / Relative weight: 1
ReflectionResolution: 2.37→64.5 Å / Num. obs: 17174 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 18.6 % / Biso Wilson estimate: 50.12 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 28.3
Reflection shellResolution: 2.37→2.5 Å / Redundancy: 19.7 % / Rmerge(I) obs: 0.52 / Mean I/σ(I) obs: 9 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.37→64.5 Å / Cor.coef. Fo:Fc: 0.9446 / Cor.coef. Fo:Fc free: 0.9292 / SU R Cruickshank DPI: 0.303 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.346 / SU Rfree Blow DPI: 0.23 / SU Rfree Cruickshank DPI: 0.222
RfactorNum. reflection% reflectionSelection details
Rfree0.2408 1005 5.89 %RANDOM
Rwork0.2054 ---
obs0.2074 17065 99.99 %-
Displacement parametersBiso mean: 47.13 Å2
Baniso -1Baniso -2Baniso -3
1-0.0499 Å20 Å20 Å2
2--0.0499 Å20 Å2
3----0.0998 Å2
Refine analyzeLuzzati coordinate error obs: 0.283 Å
Refinement stepCycle: LAST / Resolution: 2.37→64.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2414 0 18 137 2569
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012495HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.063358HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d901SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes62HARMONIC2
X-RAY DIFFRACTIONt_gen_planes371HARMONIC5
X-RAY DIFFRACTIONt_it2495HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.92
X-RAY DIFFRACTIONt_other_torsion17.92
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion313SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2850SEMIHARMONIC4
LS refinement shellResolution: 2.37→2.51 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2835 177 6.62 %
Rwork0.2179 2496 -
all0.222 2673 -
obs--99.99 %

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