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- PDB-3zlx: Crystal structure of MEK1 in complex with fragment 18 -

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Basic information

Entry
Database: PDB / ID: 3zlx
TitleCrystal structure of MEK1 in complex with fragment 18
ComponentsDUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1
KeywordsTRANSFERASE
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / labyrinthine layer development / type B pancreatic cell proliferation / MAP-kinase scaffold activity / cerebellar cortex formation / Signaling by MAP2K mutants ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / labyrinthine layer development / type B pancreatic cell proliferation / MAP-kinase scaffold activity / cerebellar cortex formation / Signaling by MAP2K mutants / regulation of Golgi inheritance / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / positive regulation of axonogenesis / regulation of stress-activated MAPK cascade / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / protein kinase activator activity / endodermal cell differentiation / face development / MAPK3 (ERK1) activation / Bergmann glial cell differentiation / MAP kinase kinase activity / thyroid gland development / Uptake and function of anthrax toxins / Schwann cell development / keratinocyte differentiation / ERK1 and ERK2 cascade / myelination / protein serine/threonine/tyrosine kinase activity / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / insulin-like growth factor receptor signaling pathway / thymus development / Signal transduction by L1 / cell motility / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / neuron differentiation / positive regulation of protein serine/threonine kinase activity / 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 / chemotaxis / MAPK cascade / cellular senescence / Signaling by BRAF and RAF1 fusions / late endosome / heart development / scaffold protein binding / protein tyrosine kinase activity / early endosome / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / negative regulation of cell population proliferation / protein phosphorylation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / centrosome / positive regulation of gene expression / positive regulation of DNA-templated transcription / Golgi apparatus / endoplasmic reticulum / signal transduction / mitochondrion / ATP binding / nucleus / plasma membrane / cytosol
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
Chem-5EZ / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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 4, 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)39,1962
Polymers38,9171
Non-polymers2791
Water1,63991
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)76.930, 76.930, 221.757
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-2037-

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 / MEK1


Mass: 38916.879 Da / Num. of mol.: 1 / 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-5EZ / 7-choro-6-[(3R)-pyrrolidin-3-ylmethoxy]isoquinolin-1(2H)-one


Mass: 278.734 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15ClN2O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 91 / 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: 2.43 Å3/Da / Density % sol: 49.46 % / 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: 0.9795
DetectorDate: Jun 7, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.2→63.81 Å / Num. obs: 20598 / % possible obs: 99.7 % / Observed criterion σ(I): 2 / Redundancy: 6.2 % / Biso Wilson estimate: 40.77 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 16.3
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 6 / % possible all: 99.8

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→49.49 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.925 / SU R Cruickshank DPI: 0.221 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.236 / SU Rfree Blow DPI: 0.187 / SU Rfree Cruickshank DPI: 0.182
RfactorNum. reflection% reflectionSelection details
Rfree0.2361 1051 5.12 %RANDOM
Rwork0.2036 ---
obs0.2053 20515 99.43 %-
Displacement parametersBiso mean: 49.59 Å2
Baniso -1Baniso -2Baniso -3
1--0.0595 Å20 Å20 Å2
2---0.0595 Å20 Å2
3---0.1189 Å2
Refine analyzeLuzzati coordinate error obs: 0.273 Å
Refinement stepCycle: LAST / Resolution: 2.2→49.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2438 0 19 91 2548
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012484HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.073342HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d898SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes63HARMONIC2
X-RAY DIFFRACTIONt_gen_planes354HARMONIC5
X-RAY DIFFRACTIONt_it2484HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.12
X-RAY DIFFRACTIONt_other_torsion17.55
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_contact2925SEMIHARMONIC4
LS refinement shellResolution: 2.2→2.32 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2582 133 4.59 %
Rwork0.2058 2764 -
all0.2081 2897 -
obs--99.43 %

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