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- PDB-7xnc: MEK1 bound to DS94070624 -

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Basic information

Entry
Database: PDB / ID: 7xnc
TitleMEK1 bound to DS94070624
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Inhibitor / Complex / ATP competitive / TRANSFERASE / 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 / type B pancreatic cell proliferation / labyrinthine layer development / 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 / type B pancreatic cell proliferation / labyrinthine layer development / 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 / protein kinase activator activity / ERBB2-ERBB3 signaling pathway / 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 / 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 / MAPK cascade / cellular senescence / Signaling by BRAF and RAF1 fusions / 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 phosphorylation / focal adhesion / protein serine kinase activity / 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
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
Similarity search - Domain/homology
Chem-GIK / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsKishikawa, S. / Takano, K. / Ubukata, O. / Hanzawa, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol.Cancer Ther. / Year: 2023
Title: Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma.
Authors: Takano, K. / Munehira, Y. / Hatanaka, M. / Murakami, R. / Shibata, Y. / Shida, T. / Takeuchi, K. / Takechi, S. / Tabata, T. / Shimada, T. / Kishikawa, S. / Matsui, Y. / Ubukata, O. / Seki, T. / Kaneta, Y.
History
DepositionApr 28, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 1, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)39,5146
Polymers38,9171
Non-polymers5975
Water1,60389
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area440 Å2
ΔGint-23 kcal/mol
Surface area14380 Å2
Unit cell
Length a, b, c (Å)77.232, 77.232, 223.220
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-511-

HOH

21A-577-

HOH

31A-589-

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 / Mutation: S298N, S299K, Y300K
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-GIK / ~{N}-[4-[[6-(3-chloranylpyridin-4-yl)-3-methyl-1~{H}-indazol-4-yl]oxy]cyclohexyl]ethanamide


Mass: 398.886 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23ClN4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-CA / CALCIUM ION


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


Mass: 18.015 Da / Num. of mol.: 89 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.47 Å3/Da / Density % sol: 50.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.75
Details: 100 mM Tris (pH 7.75), 200 mM calcium chloride, 2% DMSO, 18-20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-1A / Wavelength: 1.08 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Oct 25, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.08 Å / Relative weight: 1
ReflectionResolution: 2.1→42.85 Å / Num. obs: 24013 / % possible obs: 100 % / Redundancy: 19.7 % / Biso Wilson estimate: 38.42 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.206 / Rpim(I) all: 0.047 / Rrim(I) all: 0.212 / Net I/σ(I): 12.4 / Num. measured all: 472469
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.1-2.1620.83.6953992019190.7530.8263.7881100
8.91-42.8514.50.041594741110.0110.04251.799.2

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
Aimless0.7.7data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5BX0

5bx0


Resolution: 2.1→42.85 Å / SU ML: 0.29 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 31.57 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2512 1196 5.02 %
Rwork0.2252 22617 -
obs0.2266 23813 99.47 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 117.03 Å2 / Biso mean: 53.8059 Å2 / Biso min: 25.77 Å2
Refinement stepCycle: final / Resolution: 2.1→42.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2333 0 35 89 2457
Biso mean--48.21 48.12 -
Num. residues----311
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1-2.180.36761280.3442431255999
2.18-2.280.37091240.31812456258099
2.28-2.40.30761360.29452438257499
2.4-2.550.30381230.28282461258499
2.55-2.750.33311230.26712489261299
2.75-3.030.34911440.256624832627100
3.03-3.470.25241390.234925122651100
3.47-4.370.21381310.174725812712100
4.37-42.850.18191480.193627662914100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.19-0.2648-0.37792.48070.61482.3887-0.067-0.1422-0.2990.1492-0.08370.0484-0.0635-0.05320.1370.39230.0169-0.10250.5429-0.01570.41554.7667.497238.9061
22.5172-0.13041.18132.6772-0.30513.71610.0189-0.2624-0.06370.18810.0096-0.21140.24320.2194-0.02190.2920.0353-0.00610.3005-0.03670.3081-0.868467.643127.3475
33.44080.8516-0.89653.80021.1622.9881-0.0017-0.3096-0.3690.25990.03970.06020.4363-0.0616-0.08940.4264-0.01280.00150.35160.01080.2965-12.68859.087321.484
41.76450.07-0.57581.7919-0.16792.4908-0.00160.0991-0.2618-0.27740.0679-0.10570.25330.0572-0.0560.35730.0372-0.02670.2875-0.02840.3069-8.618865.360212.3291
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 37 through 120 )A37 - 120
2X-RAY DIFFRACTION2chain 'A' and (resid 121 through 206 )A121 - 206
3X-RAY DIFFRACTION3chain 'A' and (resid 207 through 309 )A207 - 309
4X-RAY DIFFRACTION4chain 'A' and (resid 310 through 382 )A310 - 382

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