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- PDB-7xlp: MEK1 bound to DS03090629 -

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Basic information

Entry
Database: PDB / ID: 7xlp
TitleMEK1 bound to DS03090629
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 / 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-FZC / 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 22, 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)39,5796
Polymers38,9171
Non-polymers6625
Water1,31573
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area450 Å2
ΔGint-26 kcal/mol
Surface area14290 Å2
Unit cell
Length a, b, c (Å)76.760, 76.760, 222.438
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-560-

HOH

21A-573-

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-FZC / (1~{R},3~{S})-3-[[6-[2-chloranyl-4-(4-methylpyrimidin-2-yl)oxy-phenyl]-3-methyl-1~{H}-indazol-4-yl]oxy]cyclohexan-1-amine


Mass: 463.959 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H26ClN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / 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


Mass: 18.015 Da / Num. of mol.: 73 / 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: 2.43 Å3/Da / Density % sol: 49.39 %
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: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 4, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→49.5 Å / Num. obs: 23655 / % possible obs: 99.9 % / Redundancy: 18.5 % / Biso Wilson estimate: 43.09 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.327 / Rpim(I) all: 0.079 / Rrim(I) all: 0.337 / Net I/σ(I): 9.2 / Num. measured all: 436693 / Scaling rejects: 1873
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
2.1-2.1619.67.8493712618910.7571.818.0631.799.9
8.91-49.513.40.07755024100.9970.0210.0824.999.5

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5BX0

5bx0


Resolution: 2.1→49.5 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 33.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2462 1170 5.01 %
Rwork0.2186 22170 -
obs0.22 23340 98.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 147.6 Å2 / Biso mean: 63.2445 Å2 / Biso min: 33.75 Å2
Refinement stepCycle: final / Resolution: 2.1→49.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2345 0 40 73 2458
Biso mean--55.58 56.56 -
Num. residues----312
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1-2.20.39881380.35472693283198
2.2-2.310.33751430.30442641278497
2.31-2.460.32121320.27522697282998
2.46-2.650.29941380.26592750288899
2.65-2.910.2961490.24542742289199
2.91-3.330.27051630.242927742937100
3.33-4.20.22831480.190728172965100
4.2-49.50.19691590.185530563215100
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)
12.08050.2695-0.03842.1373-0.05262.43510.1457-0.09770.10390.08140.0258-0.172-0.08790.2878-0.12280.57050.0135-0.08830.7541-0.05210.53265.729671.338737.4232
22.2302-0.2351.12261.8104-0.54954.22440.142-0.2508-0.24290.2274-0.0249-0.13060.27680.2835-0.09260.42940.0257-0.03540.4808-0.03730.48190.087964.569430.7811
32.63770.70321.5950.9566-0.02561.22570.076-0.4168-0.12270.55280.231-0.46960.3414-0.1185-0.31880.82890.0392-0.08470.60270.0350.6109-6.783551.901627.201
41.40310.343-0.62383.00220.09182.7521-0.0643-0.2449-0.1871-0.05410.12820.42190.1552-0.4534-0.06480.492-0.0161-0.02340.45240.00610.4555-17.98161.276715.2495
51.829-1.0758-0.30851.4104-0.43653.39580.0838-0.027-0.0752-0.35930.07-0.13620.10230.413-0.07780.4171-0.02380.00630.394-0.04040.4351-4.359867.998511.7744
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 37 through 92 )A37 - 92
2X-RAY DIFFRACTION2chain 'A' and (resid 93 through 206 )A93 - 206
3X-RAY DIFFRACTION3chain 'A' and (resid 207 through 241 )A207 - 241
4X-RAY DIFFRACTION4chain 'A' and (resid 242 through 331 )A242 - 331
5X-RAY DIFFRACTION5chain 'A' and (resid 332 through 382 )A332 - 382

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