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- PDB-7b94: MEK1 in complex with compound 6 -

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Basic information

Entry
Database: PDB / ID: 7b94
TitleMEK1 in complex with compound 6
ComponentsDual specificity mitogen-activated protein kinase kinase 1,Dual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE / Kinase / allosteric / fragments
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
: / 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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-T3W / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsKack, H. / Oster, L.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Fragment-Based Discovery of Novel Allosteric MEK1 Binders.
Authors: Di Fruscia, P. / Edfeldt, F. / Shamovsky, I. / Collie, G.W. / Aagaard, A. / Barlind, L. / Borjesson, U. / Hansson, E.L. / Lewis, R.J. / Nilsson, M.K. / Oster, L. / Pemberton, J. / Ripa, L. / ...Authors: Di Fruscia, P. / Edfeldt, F. / Shamovsky, I. / Collie, G.W. / Aagaard, A. / Barlind, L. / Borjesson, U. / Hansson, E.L. / Lewis, R.J. / Nilsson, M.K. / Oster, L. / Pemberton, J. / Ripa, L. / Storer, R.I. / Kack, H.
History
DepositionDec 14, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 3, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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


Theoretical massNumber of molelcules
Total (without water)75,04310
Polymers73,1162
Non-polymers1,9278
Water4,846269
1
A: Dual specificity mitogen-activated protein kinase kinase 1,Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5225
Polymers36,5581
Non-polymers9644
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dual specificity mitogen-activated protein kinase kinase 1,Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5225
Polymers36,5581
Non-polymers9644
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.280, 71.750, 157.800
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 36558.004 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q02750, mitogen-activated protein kinase kinase

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Non-polymers , 5 types, 277 molecules

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


Mass: 506.196 Da / Num. of mol.: 2 / 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.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-T3W / 2-(4-iodophenyl)-8~{H}-imidazo[1,2-c]pyrimidin-5-one


Mass: 337.116 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H8IN3O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 269 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.22 Å3/Da / Density % sol: 44.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: Crystals were obtained from hanging drops by mixing a 1:1 ratio of protein solution with well solution containing 2 M AmSO4, 0.1 M NaCl and 0.1 M Bis-tris pH 6.1-6.2
PH range: 6.1-6.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2→78.9 Å / Num. obs: 43278 / % possible obs: 99.9 % / Redundancy: 6.2 % / CC1/2: 0.99 / Rmerge(I) obs: 0.064 / Net I/σ(I): 15.3
Reflection shellResolution: 2→2.04 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.76 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 13748 / CC1/2: 0.86 / % possible all: 97.2

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3E8N

3e8n


Resolution: 2→78.9 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.928 / SU R Cruickshank DPI: 0.206 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.212 / SU Rfree Blow DPI: 0.185 / SU Rfree Cruickshank DPI: 0.183
RfactorNum. reflection% reflectionSelection details
Rfree0.265 2115 4.91 %RANDOM
Rwork0.216 ---
obs0.218 43072 96.7 %-
Displacement parametersBiso max: 148.12 Å2 / Biso mean: 52.2 Å2 / Biso min: 24.99 Å2
Baniso -1Baniso -2Baniso -3
1-0.3281 Å20 Å20 Å2
2--0.8868 Å20 Å2
3----1.2149 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: final / Resolution: 2→78.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4696 0 108 269 5073
Biso mean--64.92 53.63 -
Num. residues----596
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1763SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes851HARMONIC5
X-RAY DIFFRACTIONt_it4898HARMONIC20
X-RAY DIFFRACTIONt_nbd4SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion614SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5867SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4898HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6603HARMONIC21.2
X-RAY DIFFRACTIONt_omega_torsion3.01
X-RAY DIFFRACTIONt_other_torsion20.5
LS refinement shellResolution: 2→2.02 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3207 46 5.34 %
Rwork0.2536 816 -
all0.2572 862 -
obs--96.47 %
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)
11.46710.49390.07230.89130.1831.0909-0.01970.0336-0.04480.01520.01870.01420.01010.13920.0010.18650.02120.0236-0.0409-0.0221-0.1848-24.9374-8.655221.3745
20.79020.1745-1.02851.31430.14423.38120.06460.18920.11210.0390.01230.2074-0.2098-0.5123-0.07690.068-0.0110.0340.0041-0.001-0.1922-26.71924.5346-13.6624
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A33 - 382
2X-RAY DIFFRACTION2{ B|* }B41 - 382

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