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- PDB-5eym: MEK1 IN COMPLEX WITH BI 847325 -

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Basic information

Entry
Database: PDB / ID: 5eym
TitleMEK1 IN COMPLEX WITH BI 847325
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE / KINASE / Inhibitor
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 / MAP-kinase scaffold activity / type B pancreatic cell proliferation / 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 / MAP-kinase scaffold activity / type B pancreatic cell proliferation / cerebellar cortex formation / Signaling by MAP2K mutants / regulation of Golgi inheritance / spindle pole body / 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 / MAPK3 (ERK1) activation / endodermal cell differentiation / face development / MAP kinase kinase activity / Bergmann glial cell differentiation / Uptake and function of anthrax toxins / thyroid gland development / Schwann cell development / keratinocyte differentiation / protein serine/threonine/tyrosine kinase activity / myelination / ERK1 and ERK2 cascade / 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 / positive regulation of protein serine/threonine kinase activity / 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 / chemotaxis / cellular senescence / Signaling by BRAF and RAF1 fusions / MAPK cascade / late endosome / heart development / scaffold protein binding / protein tyrosine kinase activity / positive regulation of ERK1 and ERK2 cascade / early endosome / protein kinase activity / negative regulation of cell population proliferation / 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 ...: / 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-5U5 / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsBader, G. / Reiser, U. / Zahn, S.K. / Treu, M.
CitationJournal: Mol.Cancer Ther. / Year: 2016
Title: Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases.
Authors: Sini, P. / Gurtler, U. / Zahn, S.K. / Baumann, C. / Rudolph, D. / Baumgartinger, R. / Strauss, E. / Haslinger, C. / Tontsch-Grunt, U. / Waizenegger, I.C. / Solca, F. / Bader, G. / Zoephel, A. ...Authors: Sini, P. / Gurtler, U. / Zahn, S.K. / Baumann, C. / Rudolph, D. / Baumgartinger, R. / Strauss, E. / Haslinger, C. / Tontsch-Grunt, U. / Waizenegger, I.C. / Solca, F. / Bader, G. / Zoephel, A. / Treu, M. / Reiser, U. / Garin-Chesa, P. / Boehmelt, G. / Kraut, N. / Quant, J. / Adolf, G.R.
History
DepositionNov 25, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 17, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: 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 / diffrn_radiation_wavelength / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
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_asym_id / _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_asym_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_asym_id / _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_asym_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

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


Theoretical massNumber of molelcules
Total (without water)81,1627
Polymers80,1122
Non-polymers1,0495
Water30617
1
A: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6415
Polymers40,0561
Non-polymers5854
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5212
Polymers40,0561
Non-polymers4651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)78.760, 78.760, 223.412
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61

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Components

#1: Protein Dual specificity mitogen-activated protein kinase kinase 1 / MKK1 / ERK activator kinase 1 / MAPK/ERK kinase 1 / MEK 1


Mass: 40056.168 Da / Num. of mol.: 2 / Fragment: UNP residues 35-393 / Mutation: S298N, S299K, Y300F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-5U5 / 3-[(3~{Z})-3-[[[4-[(dimethylamino)methyl]phenyl]amino]-phenyl-methylidene]-2-oxidanylidene-1~{H}-indol-6-yl]-~{N}-ethyl-prop-2-ynamide


Mass: 464.558 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H28N4O2
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 2.61 Å3/Da / Density % sol: 52.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 18 % PEG 4000, 100 mM Tris, 300 mM NaCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Oct 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→68.21 Å / Num. obs: 20634 / % possible obs: 97.2 % / Observed criterion σ(I): 0 / Redundancy: 2.6 % / Rmerge(I) obs: 0.16 / Rsym value: 0.12 / Net I/σ(I): 5.5
Reflection shellResolution: 2.7→2.89 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.7 / Mean I/σ(I) obs: 1.1 / Rejects: 0 / % possible all: 97.4

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Processing

Software
NameVersionClassification
REFMAC5.5.0088refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3EQC

3eqc


Resolution: 2.7→68.21 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.871 / SU B: 40.028 / SU ML: 0.381 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.015 / ESU R Free: 0.417 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3077 1357 6.6 %RANDOM
Rwork0.2426 ---
obs0.2468 19120 99.24 %-
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 max: 64.25 Å2 / Biso mean: 19.644 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-5.01 Å22.5 Å20 Å2
2--5.01 Å20 Å2
3----7.51 Å2
Refinement stepCycle: final / Resolution: 2.7→68.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2308 0 69 17 2394
Biso mean--49.15 9.84 -
Num. residues----584
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0224637
X-RAY DIFFRACTIONr_bond_other_d0.0010.023237
X-RAY DIFFRACTIONr_angle_refined_deg0.9011.9976261
X-RAY DIFFRACTIONr_angle_other_deg1.25237839
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4075576
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.53724.378185
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.62615797
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8891524
X-RAY DIFFRACTIONr_chiral_restr0.0510.2703
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0215088
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02902
X-RAY DIFFRACTIONr_mcbond_it0.97222912
X-RAY DIFFRACTIONr_mcbond_other0.12421178
X-RAY DIFFRACTIONr_mcangle_it1.77334665
X-RAY DIFFRACTIONr_scbond_it2.45841725
X-RAY DIFFRACTIONr_scangle_it3.86361596
LS refinement shellResolution: 2.701→2.771 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.459 83 -
Rwork0.409 1216 -
all-1299 -
obs--100 %

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