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- PDB-7pqv: MEK1 IN COMPLEX WITH COMPOUND 7 -

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Basic information

Entry
Database: PDB / ID: 7pqv
TitleMEK1 IN COMPLEX WITH COMPOUND 7
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsSIGNALING PROTEIN / MEK1 MITOGEN-ACTIVATED PROTEIN KINASE 1 / KINASE INHIBITOR / ANTI-CANCER DRUG
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
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-80C / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 Å
AuthorsMoebitz, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action.
Authors: Poddutoori, R. / Aardalen, K. / Aithal, K. / Barahagar, S.S. / Belliappa, C. / Bock, M. / Chelur, S. / Gerken, A. / Gopinath, S. / Gruenenfelder, B. / Kiffe, M. / Krishnaswami, M. / ...Authors: Poddutoori, R. / Aardalen, K. / Aithal, K. / Barahagar, S.S. / Belliappa, C. / Bock, M. / Chelur, S. / Gerken, A. / Gopinath, S. / Gruenenfelder, B. / Kiffe, M. / Krishnaswami, M. / Langowski, J. / Madapa, S. / Narayanan, K. / Pandit, C. / Panigrahi, S.K. / Perrone, M. / Potakamuri, R.K. / Ramachandra, M. / Ramanathan, A. / Ramos, R. / Sager, E. / Samajdar, S. / Subramanya, H.S. / Thimmasandra, D.S. / Venetsanakos, E. / Mobitz, H.
History
DepositionSep 20, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 16, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)39,0235
Polymers38,5071
Non-polymers5154
Water3,423190
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-22 kcal/mol
Surface area15120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.158, 77.158, 222.649
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-402-

CA

21A-576-

HOH

31A-617-

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: 38507.414 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
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-80C / 8-(2-chloranyl-4-methoxy-phenyl)-7-fluoranyl-1-piperidin-4-yl-imidazo[4,5-c]quinoline


Mass: 410.872 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20ClFN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 190 / 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: 2

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Sample preparation

CrystalDensity Matthews: 1.24 Å3/Da / Density % sol: 54 %
Crystal growTemperature: 310 K / Method: batch mode
Details: The purified protein was used in crystallisation trials employing both, a standard screen with approximately 1200 different conditions, as well as crystallisation conditions identified using ...Details: The purified protein was used in crystallisation trials employing both, a standard screen with approximately 1200 different conditions, as well as crystallisation conditions identified using literature data. Condi- tions initially obtained have been optimised using standard strategies, systematically varying parameters critically influencing crystallisation, such as temperature, protein concentration, drop ratio, and others. These conditions were also refined by systematically varying pH or precipitant concentrations.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9798 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 2, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9798 Å / Relative weight: 1
ReflectionResolution: 2.13→66.82 Å / Num. obs: 22886 / % possible obs: 97.2 % / Redundancy: 5.7 % / Rrim(I) all: 0.081 / Rsym value: 0.075 / Net I/σ(I): 14.66
Reflection shellResolution: 2.13→2.3 Å / Redundancy: 5.9 % / Mean I/σ(I) obs: 3.07 / Num. unique obs: 4328 / Rrim(I) all: 0.479 / Rsym value: 0.44 / % possible all: 95.6

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.2.0005refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.13→66.82 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.905 / SU B: 7.929 / SU ML: 0.195 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.259 / ESU R Free: 0.223 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2869 1614 7.3 %RANDOM
Rwork0.2353 ---
obs0.2389 20635 97.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 81.22 Å2 / Biso mean: 34.619 Å2 / Biso min: 17.76 Å2
Baniso -1Baniso -2Baniso -3
1-2.7 Å21.35 Å20 Å2
2--2.7 Å20 Å2
3----4.06 Å2
Refinement stepCycle: final / Resolution: 2.13→66.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2441 0 32 190 2663
Biso mean--39.06 40.06 -
Num. residues----310
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222427
X-RAY DIFFRACTIONr_bond_other_d0.0020.022265
X-RAY DIFFRACTIONr_angle_refined_deg1.0771.9923281
X-RAY DIFFRACTIONr_angle_other_deg0.89735240
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1675309
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.55823.73691
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.46815415
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.2281514
X-RAY DIFFRACTIONr_chiral_restr0.0610.2368
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.022688
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02476
X-RAY DIFFRACTIONr_nbd_refined0.1460.2461
X-RAY DIFFRACTIONr_nbd_other0.1230.22126
X-RAY DIFFRACTIONr_nbtor_refined0.1490.21168
X-RAY DIFFRACTIONr_nbtor_other0.0720.21239
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0820.2147
X-RAY DIFFRACTIONr_metal_ion_refined0.0590.26
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1530.211
X-RAY DIFFRACTIONr_symmetry_vdw_other0.0930.237
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0450.29
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.0220.22
LS refinement shellResolution: 2.13→2.185 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.377 121 -
Rwork0.335 1429 -
all-1550 -
obs--94.11 %

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