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- PDB-7m0x: Crystal structure of the BRAF:MEK1 kinases in complex with AMPPNP... -

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Basic information

Entry
Database: PDB / ID: 7m0x
TitleCrystal structure of the BRAF:MEK1 kinases in complex with AMPPNP and PD0325901
Components
  • Dual specificity mitogen-activated protein kinase kinase 1
  • Serine/threonine-protein kinase B-raf
KeywordsTRANSFERASE / BRAF / MEK1
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / JUN kinase kinase activity / CD4-positive, alpha-beta T cell differentiation / regulation of axon regeneration / mitogen-activated protein kinase kinase / placenta blood vessel development / MAP-kinase scaffold activity / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / labyrinthine layer development ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / JUN kinase kinase activity / CD4-positive, alpha-beta T cell differentiation / regulation of axon regeneration / mitogen-activated protein kinase kinase / placenta blood vessel development / MAP-kinase scaffold activity / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / labyrinthine layer development / negative regulation of synaptic vesicle exocytosis / cerebellar cortex formation / type B pancreatic cell proliferation / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / Signaling by MAP2K mutants / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / negative regulation of fibroblast migration / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / positive regulation of axonogenesis / regulation of Golgi inheritance / regulation of T cell differentiation / trachea formation / mitogen-activated protein kinase kinase binding / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / MAPK3 (ERK1) activation / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / positive regulation of axon regeneration / stress fiber assembly / endodermal cell differentiation / face development / MAP kinase kinase activity / Bergmann glial cell differentiation / synaptic vesicle exocytosis / Uptake and function of anthrax toxins / thyroid gland development / somatic stem cell population maintenance / protein kinase activator activity / MAP kinase kinase kinase activity / positive regulation of protein serine/threonine kinase activity / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / Schwann cell development / keratinocyte differentiation / response to cAMP / positive regulation of peptidyl-serine phosphorylation / positive regulation of stress fiber assembly / positive regulation of substrate adhesion-dependent cell spreading / myelination / ERK1 and ERK2 cascade / protein serine/threonine/tyrosine kinase activity / substrate adhesion-dependent cell spreading / insulin-like growth factor receptor signaling pathway / cellular response to calcium ion / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / thymus development / animal organ morphogenesis / Signal transduction by L1 / cell motility / RAF activation / cellular response to nerve growth factor stimulus / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / response to peptide hormone / centriolar satellite / long-term synaptic potentiation / epidermal growth factor receptor signaling pathway / neuron differentiation / chemotaxis / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / cellular senescence / Signaling by BRAF and RAF1 fusions / MAPK cascade / late endosome / cellular response to xenobiotic stimulus / presynapse / T cell receptor signaling pathway / regulation of cell population proliferation / T cell differentiation in thymus / heart development / cell body / protein tyrosine kinase activity / scaffold protein binding / negative regulation of neuron apoptotic process / eukaryotic translation initiation factor 2alpha kinase activity
Similarity search - Function
: / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / : / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. ...: / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / : / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ubiquitin-like domain superfamily / 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-4BM / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Serine/threonine-protein kinase B-raf / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.47 Å
AuthorsLi, K. / Gonzalez Del-Pino, G. / Ha, B.H. / Park, E. / Eck, M.J.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P50 CA165962 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R50 CA221830 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 CA242461 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2021
Title: Allosteric MEK inhibitors act on BRAF/MEK complexes to block MEK activation.
Authors: Gonzalez-Del Pino, G.L. / Li, K. / Park, E. / Schmoker, A.M. / Ha, B.H. / Eck, M.J.
History
DepositionMar 11, 2021Deposition site: RCSB / Processing site: RCSB
SupersessionApr 21, 2021ID: 6V2V
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 3, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 10, 2021Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Oct 18, 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

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Assembly

Deposited unit
A: Serine/threonine-protein kinase B-raf
B: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,84312
Polymers75,8882
Non-polymers1,95510
Water3,081171
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5680 Å2
ΔGint-68 kcal/mol
Surface area25080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.527, 116.527, 130.712
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Serine/threonine-protein kinase B-raf / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 32098.104 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Plasmid: pFastBac Dual / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Protein Dual specificity mitogen-activated protein kinase kinase 1 / MKK1 / ERK activator kinase 1 / MAPK/ERK kinase 1 / MEK 1


Mass: 43790.281 Da / Num. of mol.: 1 / Mutation: S218A, S222A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Plasmid: pFastBac Dual / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q02750, mitogen-activated protein kinase kinase

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Non-polymers , 7 types, 181 molecules

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


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-4BM / N-{[(2R)-2,3-dihydroxypropyl]oxy}-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide


Mass: 482.193 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H14F3IN2O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / 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: 3.38 Å3/Da / Density % sol: 63.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 100 mM Bis-Tris pH 6.4, 200 mM Ammonium Sulfate, and 22% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.978 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 2.47→43.571 Å / Num. obs: 37262 / % possible obs: 99.94 % / Redundancy: 19.8 % / Biso Wilson estimate: 45.12 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.179 / Rpim(I) all: 0.0411 / Rrim(I) all: 0.184 / Net I/σ(I): 14.8
Reflection shellResolution: 2.47→2.56 Å / Mean I/σ(I) obs: 2 / Num. unique obs: 3669 / CC1/2: 0.717 / Rpim(I) all: 0.459

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6PP9

6pp9


Resolution: 2.47→43.57 Å / SU ML: 0.2679 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21.4072
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2151 1906 5.12 %
Rwork0.1781 35352 -
obs0.18 37258 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 48.58 Å2
Refinement stepCycle: LAST / Resolution: 2.47→43.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4654 0 113 171 4938
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094883
X-RAY DIFFRACTIONf_angle_d1.04736605
X-RAY DIFFRACTIONf_chiral_restr0.0563725
X-RAY DIFFRACTIONf_plane_restr0.0069831
X-RAY DIFFRACTIONf_dihedral_angle_d20.42461845
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.47-2.530.31261570.23382466X-RAY DIFFRACTION100
2.53-2.60.23931280.21982471X-RAY DIFFRACTION100
2.6-2.680.26621350.22462512X-RAY DIFFRACTION100
2.68-2.760.26711560.21222477X-RAY DIFFRACTION100
2.76-2.860.27331260.21432500X-RAY DIFFRACTION99.92
2.86-2.980.21761520.20492499X-RAY DIFFRACTION100
2.98-3.110.25011290.20412498X-RAY DIFFRACTION100
3.11-3.280.26351270.1862514X-RAY DIFFRACTION99.96
3.28-3.480.24721050.18112561X-RAY DIFFRACTION99.96
3.48-3.750.22391230.17452540X-RAY DIFFRACTION100
3.75-4.130.18381520.15322505X-RAY DIFFRACTION100
4.13-4.720.18111360.13932555X-RAY DIFFRACTION99.96
4.72-5.950.1871570.16182561X-RAY DIFFRACTION99.96
5.95-43.570.18641230.18222693X-RAY DIFFRACTION99.79

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