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- PDB-7m0y: Crystal structure of the BRAF:MEK1 kinases in complex with AMPPNP... -

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Basic information

Entry
Database: PDB / ID: 7m0y
TitleCrystal structure of the BRAF:MEK1 kinases in complex with AMPPNP and Trametinib
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 / 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 / CD4-positive, alpha-beta T cell differentiation / positive regulation of axon regeneration / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development ...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 / CD4-positive, alpha-beta T cell differentiation / positive regulation of axon regeneration / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development / MAP-kinase scaffold activity / positive regulation of muscle contraction / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / regulation of axon regeneration / cerebellar cortex formation / melanosome transport / type B pancreatic cell proliferation / Signalling to p38 via RIT and RIN / head morphogenesis / ARMS-mediated activation / myeloid progenitor cell differentiation / central nervous system neuron differentiation / endothelial cell apoptotic process / Signaling by MAP2K mutants / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of D-glucose transmembrane transport / negative regulation of fibroblast migration / vesicle transport along microtubule / establishment of protein localization to membrane / positive regulation of axonogenesis / positive regulation of Ras protein signal transduction / regulation of Golgi inheritance / mitogen-activated protein kinase kinase kinase binding / triglyceride homeostasis / regulation of T cell differentiation / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / mitogen-activated protein kinase kinase binding / regulation of stress-activated MAPK cascade / Frs2-mediated activation / stress fiber assembly / 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 / synaptic vesicle exocytosis / protein kinase activator activity / somatic stem cell population maintenance / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / positive regulation of protein serine/threonine kinase activity / postsynaptic modulation of chemical synaptic transmission / response to axon injury / negative regulation of endothelial cell apoptotic process / Schwann cell development / response to cAMP / keratinocyte differentiation / MAP3K8 (TPL2)-dependent MAPK1/3 activation / positive regulation of stress fiber assembly / neuron projection morphogenesis / ERK1 and ERK2 cascade / myelination / positive regulation of autophagy / positive regulation of substrate adhesion-dependent cell spreading / protein serine/threonine/tyrosine kinase activity / substrate adhesion-dependent cell spreading / dendrite cytoplasm / insulin-like growth factor receptor signaling pathway / cellular response to calcium ion / response to glucocorticoid / histone H4S1 kinase activity / : / histone H3S57 kinase activity / histone H2BS14 kinase activity / histone H3S28 kinase activity / thymus development / histone H2AS1 kinase activity / histone H3T6 kinase activity / protein serine/threonine kinase activator activity / ribosomal protein S6 kinase activity / histone H2AT120 kinase activity / histone H2BS36 kinase activity / animal organ morphogenesis / eukaryotic translation initiation factor 2alpha kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H3S10 kinase activity / AMP-activated protein kinase activity / histone H3T11 kinase activity / histone H3T3 kinase activity / 3-phosphoinositide-dependent protein 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 / Trametinib / 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: 3.45 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: 6V2Y
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)77,6618
Polymers75,8882
Non-polymers1,7726
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4960 Å2
ΔGint-54 kcal/mol
Surface area25340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.716, 116.716, 129.483
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"

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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 / 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 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q02750, mitogen-activated protein kinase kinase

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Non-polymers , 4 types, 6 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-QOM / Trametinib / N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide


Mass: 615.395 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H23FIN5O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, anticancer, inhibitor*YM

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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: 3.35 Å3/Da / Density % sol: 67.94 %
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: 0.978 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 14, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 3.45→47.08 Å / Num. obs: 13509 / % possible obs: 97.53 % / Redundancy: 4.8 % / Biso Wilson estimate: 86.09 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.1498 / Rpim(I) all: 0.0755 / Rrim(I) all: 0.1685 / Net I/σ(I): 9.4
Reflection shellResolution: 3.451→3.575 Å / Rmerge(I) obs: 0.6754 / Mean I/σ(I) obs: 2.28 / Num. unique obs: 1329 / CC1/2: 0.748 / Rpim(I) all: 0.3383 / Rrim(I) all: 0.758 / % possible all: 98.37

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6PP9

6pp9


Resolution: 3.45→47.08 Å / SU ML: 0.2753 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.1489
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2178 637 4.72 %
Rwork0.1953 12872 -
obs0.1964 13509 97.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 77.48 Å2
Refinement stepCycle: LAST / Resolution: 3.45→47.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4620 0 106 0 4726
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00484827
X-RAY DIFFRACTIONf_angle_d0.77396529
X-RAY DIFFRACTIONf_chiral_restr0.0403712
X-RAY DIFFRACTIONf_plane_restr0.0097821
X-RAY DIFFRACTIONf_dihedral_angle_d19.81251820
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.45-3.720.28511090.28462562X-RAY DIFFRACTION97.95
3.72-4.090.23281300.22072527X-RAY DIFFRACTION97.9
4.09-4.680.22561280.17582573X-RAY DIFFRACTION98.29
4.68-5.890.21981250.18672576X-RAY DIFFRACTION97.65
5.9-47.080.18441450.17152634X-RAY DIFFRACTION96.29

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