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- PDB-7m0v: Crystal structure of the BRAF:MEK1 kinases in complex with AMPPNP... -

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Basic information

Entry
Database: PDB / ID: 7m0v
TitleCrystal structure of the BRAF:MEK1 kinases in complex with AMPPNP and Cobimetinib
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 / mitogen-activated protein kinase kinase binding / trachea formation / 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 / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / Schwann cell development / keratinocyte differentiation / response to cAMP / positive regulation of stress fiber assembly / positive regulation of protein serine/threonine kinase activity / positive regulation of substrate adhesion-dependent cell spreading / myelination / ERK1 and ERK2 cascade / protein serine/threonine/tyrosine kinase activity / substrate adhesion-dependent cell spreading / cellular response to calcium ion / insulin-like growth factor receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / 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 / long-term synaptic potentiation / 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 / neuron differentiation / epidermal growth factor receptor signaling pathway / response to peptide hormone / Signaling by RAF1 mutants / chemotaxis / 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 / MAPK cascade / cellular senescence / Signaling by BRAF and RAF1 fusions / 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 / ciliary basal body / 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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-EUI / 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: 3.16 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: 6V2Z
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)77,4817
Polymers75,8882
Non-polymers1,5925
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4640 Å2
ΔGint-37 kcal/mol
Surface area25030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.144, 116.144, 129.886
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

#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 / Cell line (production host): Sf9 / 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: pAC8 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#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-EUI / [3,4-BIS(FLUORANYL)-2-[(2-FLUORANYL-4-IODANYL-PHENYL)AMINO]PHENYL]-[3-OXIDANYL-3-[(2S)-PIPERIDIN-2-YL]AZETIDIN-1-YL]METHANONE


Mass: 531.310 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21F3IN3O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, anticancer, inhibitor*YM
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: 3.33 Å3/Da / Density % sol: 63.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 100 mM Tris 8.5, 200 mM Lithium Sulfate and 22% PEG 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.16→43.3 Å / Num. obs: 17794 / % possible obs: 99.88 % / Redundancy: 19.6 % / Biso Wilson estimate: 111.13 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.1543 / Rpim(I) all: 0.03577 / Rrim(I) all: 0.1543 / Net I/σ(I): 18.76
Reflection shellResolution: 3.16→3.273 Å / Mean I/σ(I) obs: 1.63 / Num. unique obs: 1747 / CC1/2: 0.745 / Rpim(I) all: 0.472

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Processing

Software
NameVersionClassification
PHENIX1.19_4092refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6PP9

6pp9


Resolution: 3.16→43.3 Å / SU ML: 0.4 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2336 818 4.6 %
Rwork0.1859 16975 -
obs0.188 17793 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 208.16 Å2 / Biso mean: 107.1681 Å2 / Biso min: 66.65 Å2
Refinement stepCycle: final / Resolution: 3.16→43.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4623 0 94 0 4717
Biso mean--103.11 --
Num. residues----584
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
3.16-3.360.33321430.290127752918
3.36-3.620.30421450.223727692914
3.62-3.980.27941240.236528082932
3.98-4.560.21421570.167127792936
4.56-5.740.23871260.193928582984
5.74-43.30.19471230.152329863109
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)
13.15170.05581.28382.38050.34083.6940.1159-0.4121-0.12380.0597-0.08350.3550.0843-0.4628-0.01690.7919-0.03990.05850.7731-0.0310.857438.1882-25.084-8.1437
21.2026-0.15570.47922.58120.18383.64450.0708-0.07490.15890.2256-0.1127-0.0969-0.18440.3920.03290.8121-0.12330.09030.785-0.02420.69563.7966-20.613314.7108
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'A' and resid 449 through 722)A449 - 722
2X-RAY DIFFRACTION2(chain 'B' and resid 42 through 383)B42 - 383

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