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- PDB-3wig: Human MEK1 kinase in complex with CH5126766 and MgAMP-PNP -

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Basic information

Entry
Database: PDB / ID: 3wig
TitleHuman MEK1 kinase in complex with CH5126766 and MgAMP-PNP
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / kinase inhibitor / allosteric / TRANSFERASE-TRANSFERASE INHIBITOR complex
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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-CHU / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.7 Å
AuthorsLukacs, C.M. / Janson, C. / Schuck, V.
CitationJournal: Cancer Cell / Year: 2014
Title: Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors
Authors: Lito, P. / Saborowski, A. / Yue, J. / Solomon, M. / Joseph, E. / Gadal, S. / Saborowski, M. / Kastenhuber, E. / Fellmann, C. / Ohara, K. / Morikami, K. / Miura, T. / Lukacs, C. / Ishii, N. / Lowe, S. / Rosen, N.
History
DepositionSep 12, 2013Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 4, 2014Provider: repository / Type: Initial release
Revision 1.1Aug 16, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Dec 25, 2019Group: Data collection / Database references / Category: reflns / reflns_shell / struct_ref_seq_dif
Item: _reflns.pdbx_Rmerge_I_obs / _reflns.pdbx_Rrim_I_all ..._reflns.pdbx_Rmerge_I_obs / _reflns.pdbx_Rrim_I_all / _reflns_shell.Rmerge_I_obs / _reflns_shell.pdbx_Rrim_I_all / _struct_ref_seq_dif.details
Revision 1.4Mar 20, 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_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_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)35,61310
Polymers34,2391
Non-polymers1,3739
Water28816
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
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)71,22620
Polymers68,4792
Non-polymers2,74718
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555x-y,-y,-z+2/31
Buried area3560 Å2
ΔGint-10 kcal/mol
Surface area24440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)136.366, 136.366, 59.764
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 1 types, 1 molecules A

#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: 34239.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: UNP RESIDUES 62-270, 303-393 / Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q02750, mitogen-activated protein kinase kinase

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Non-polymers , 6 types, 25 molecules

#2: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-CHU / N-(3-fluoro-4-{[4-methyl-2-oxo-7-(pyrimidin-2-yloxy)-2H-chromen-3-yl]methyl}pyridin-2-yl)-N'-methylsulfuric diamide / CH5126766


Mass: 471.462 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18FN5O5S
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#6: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / 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: 4.68 Å3/Da / Density % sol: 73.75 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 4.2
Details: 7.5-10% PEG 8000, 0.2M NaCl, 0.2M Ammonium sulfate, 0.1M citrate buffer, pH 4.2, vapor diffusion, sitting drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97929 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Mar 27, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 2.45→34.1 Å / Num. obs: 45559 / % possible obs: 99.7 % / Redundancy: 5.1 % / Rrim(I) all: 0.112 / Rsym value: 0.091 / Net I/σ(I): 8.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.45-2.584.70.63133566511.4191.0931.499.5
2.58-2.744.80.93009562900.6442.299.5
2.74-2.934.91.92888759260.3693.799.7
2.93-3.1653.42788355360.2076.299.9
3.16-3.465.26.12657650700.1159.7100
3.46-3.875.48.32470445820.0813100
3.87-4.475.411.12196340420.05715.1100
4.47-5.485.511.51878434410.05216.3100
5.48-7.755.59.91438526350.06216.9100
7.75-34.14.812.8669913860.04216.495.4

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.94 Å27.37 Å
Translation2.94 Å27.37 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.2.5data scaling
MOLREPphasing
CNSrefinement
PDB_EXTRACT3.11data extraction
DENZOdata reduction
SCALEPACKdata scaling
CNX2005refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→27.37 Å / Rfactor Rfree error: 0.008 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8036 / Data cutoff high absF: 1132132 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.25 896 5 %RANDOM
Rwork0.215 ---
obs0.217 17775 99.7 %-
all-17775 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 43.31 Å2 / ksol: 0.3505 e/Å3
Displacement parametersBiso max: 94.07 Å2 / Biso mean: 56.8507 Å2 / Biso min: 34.25 Å2
Baniso -1Baniso -2Baniso -3
1--16.53 Å2-2.65 Å20 Å2
2---16.53 Å20 Å2
3---33.06 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.42 Å0.35 Å
Luzzati d res low-5 Å
Luzzati sigma a0.53 Å0.49 Å
Refinement stepCycle: LAST / Resolution: 2.7→27.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2179 0 83 16 2278
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_dihedral_angle_d20.4
X-RAY DIFFRACTIONc_improper_angle_d0.62
X-RAY DIFFRACTIONc_mcbond_it1.171.5
X-RAY DIFFRACTIONc_mcangle_it2.022
X-RAY DIFFRACTIONc_scbond_it1.92
X-RAY DIFFRACTIONc_scangle_it2.982.5
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 17

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.7-2.760.3096430.335310001043
2.76-2.820.3174500.31759811031
2.82-2.880.3948480.31639981046
2.88-2.950.3434460.30669611007
2.95-3.030.3685640.30939861050
3.03-3.120.3337620.28589901052
3.12-3.220.2924400.27729801020
3.22-3.340.3125560.26319861042
3.34-3.470.3034540.25629871041
3.47-3.630.2436590.23499991058
3.63-3.820.265520.19159791031
3.82-4.060.2296530.17739941047
4.06-4.370.227440.162910061050
4.37-4.810.1939550.14669971052
4.81-5.510.1807540.172210141068
5.51-6.940.2539620.21499991061
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4lig.paramlig.top
X-RAY DIFFRACTION5anp2.paramanp2.top

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