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- PDB-9o0u: Crystal structure of CRAF/MEK1 complex with PLX4720 and CH5126766 -

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Basic information

Entry
Database: PDB / ID: 9o0u
TitleCrystal structure of CRAF/MEK1 complex with PLX4720 and CH5126766
Components
  • Dual specificity mitogen-activated protein kinase kinase 1
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsTRANSFERASE / CRAF-MEK1 complex / MAPK pathway
Function / homology
Function and homology information


death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / regulation of vascular associated smooth muscle contraction / intermediate filament cytoskeleton organization / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development ...death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / regulation of vascular associated smooth muscle contraction / intermediate filament cytoskeleton organization / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development / MAP-kinase scaffold activity / positive regulation of muscle contraction / regulation of axon regeneration / cerebellar cortex formation / labyrinthine layer development / regulation of Rho protein signal transduction / melanosome transport / type B pancreatic cell proliferation / Signaling by MAP2K mutants / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / vesicle transport along microtubule / positive regulation of axonogenesis / positive regulation of Ras protein signal transduction / insulin secretion involved in cellular response to glucose stimulus / regulation of Golgi inheritance / mitogen-activated protein kinase kinase kinase binding / central nervous system neuron differentiation / triglyceride homeostasis / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / IFNG signaling activates MAPKs / regulation of stress-activated MAPK cascade / Frs2-mediated activation / GP1b-IX-V activation signalling / MAPK3 (ERK1) activation / ERBB2-ERBB3 signaling pathway / neurotrophin TRK receptor signaling pathway / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / pseudopodium / face development / endodermal cell differentiation / MAP kinase kinase activity / Bergmann glial cell differentiation / positive regulation of ATP biosynthetic process / regulation of cell differentiation / thyroid gland development / Uptake and function of anthrax toxins / positive regulation of protein serine/threonine kinase activity / extrinsic apoptotic signaling pathway via death domain receptors / somatic stem cell population maintenance / protein kinase activator activity / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / type II interferon-mediated signaling pathway / negative regulation of protein-containing complex assembly / Schwann cell development / response to axon injury / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / keratinocyte differentiation / neuron projection morphogenesis / response to muscle stretch / ERK1 and ERK2 cascade / myelination / positive regulation of autophagy / protein serine/threonine/tyrosine kinase activity / CD209 (DC-SIGN) signaling / dendrite cytoplasm / insulin-like growth factor receptor signaling pathway / response to glucocorticoid / MAP3K8 (TPL2)-dependent MAPK1/3 activation / thymus development / adenylate cyclase activator activity / protein serine/threonine kinase activator activity / Signal transduction by L1 / cell motility / positive regulation of transcription elongation by RNA polymerase II / wound healing / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / small GTPase binding / Stimuli-sensing channels / neuron differentiation / chemotaxis / Negative regulation of MAPK pathway / 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 / cellular senescence / Signaling by BRAF and RAF1 fusions / insulin receptor signaling pathway / late endosome / MAPK cascade / heart development / response to oxidative stress / protein tyrosine 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 / Ubiquitin-like domain superfamily / 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-324 / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-CHU / RAF proto-oncogene serine/threonine-protein kinase / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.91 Å
AuthorsJang, D.M. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R35CA242461-06 United States
CitationJournal: J.Biol.Chem. / Year: 2025
Title: Characterization and inhibitor sensitivity of ARAF, BRAF, and CRAF kinases.
Authors: Tkacik, E. / Jang, D.M. / Boxer, K. / Ha, B.H. / Eck, M.J.
History
DepositionApr 3, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 15, 2025Provider: repository / Type: Initial release
Revision 1.1Oct 22, 2025Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: RAF proto-oncogene serine/threonine-protein kinase
B: Dual specificity mitogen-activated protein kinase kinase 1
C: RAF proto-oncogene serine/threonine-protein kinase
D: Dual specificity mitogen-activated protein kinase kinase 1
E: RAF proto-oncogene serine/threonine-protein kinase
F: Dual specificity mitogen-activated protein kinase kinase 1
G: RAF proto-oncogene serine/threonine-protein kinase
H: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)306,37517
Polymers302,3278
Non-polymers4,0479
Water79344
1
A: RAF proto-oncogene serine/threonine-protein kinase
B: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4674
Polymers75,5822
Non-polymers8852
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: RAF proto-oncogene serine/threonine-protein kinase
D: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4674
Polymers75,5822
Non-polymers8852
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
E: RAF proto-oncogene serine/threonine-protein kinase
F: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,4674
Polymers75,5822
Non-polymers8852
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
G: RAF proto-oncogene serine/threonine-protein kinase
H: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,9735
Polymers75,5822
Non-polymers1,3913
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)180.990, 180.990, 367.020
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Space group name HallP652(x,y,z+1/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+1/3
#8: -x,-y,z+1/2
#9: y,x,-z+2/3
#10: -y,-x,-z+1/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+5/6

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Components

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Protein , 2 types, 8 molecules ACEGBDFH

#1: Protein
RAF proto-oncogene serine/threonine-protein kinase / Proto-oncogene c-RAF / cRaf / Raf-1


Mass: 32005.803 Da / Num. of mol.: 4 / Mutation: Y340D, Y341D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAF1, RAF / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04049, non-specific serine/threonine protein kinase
#2: 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: 43576.039 Da / Num. of mol.: 4 / Mutation: S218A, S222A
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 , 4 types, 53 molecules

#3: Chemical
ChemComp-324 / N-{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl}propane-1-sulfonamide


Mass: 413.826 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C17H14ClF2N3O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CHU / N-(3-fluoro-4-{[4-methyl-2-oxo-7-(pyrimidin-2-yloxy)-2H-chromen-3-yl]methyl}pyridin-2-yl)-N'-methylsulfuric diamide / CH5126766


Mass: 471.462 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C21H18FN5O5S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C10H17N6O12P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.87 Å3/Da / Density % sol: 57.14 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 18% PEG 3350, 0.1 M Sodium citrate pH 5.6, 4% Tacsimate pH 5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.9202 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 8, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9202 Å / Relative weight: 1
ReflectionResolution: 2.91→50 Å / Num. obs: 147338 / % possible obs: 99.7 % / Redundancy: 4.79 % / Biso Wilson estimate: 67.3 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.132 / Net I/σ(I): 9.63
Reflection shellResolution: 2.91→3.08 Å / Redundancy: 4.69 % / Rmerge(I) obs: 1.044 / Num. unique obs: 23539 / CC1/2: 0.995 / % possible all: 98.8

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.91→46.1 Å / SU ML: 0.3576 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.7681
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2639 3911 5 %
Rwork0.2302 74312 -
obs0.2318 78223 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 80.51 Å2
Refinement stepCycle: LAST / Resolution: 2.91→46.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms18472 0 271 44 18787
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006719159
X-RAY DIFFRACTIONf_angle_d1.086125863
X-RAY DIFFRACTIONf_chiral_restr0.06532819
X-RAY DIFFRACTIONf_plane_restr0.00813282
X-RAY DIFFRACTIONf_dihedral_angle_d15.43367241
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.91-2.940.37251310.35742492X-RAY DIFFRACTION95.17
2.94-2.980.38451380.33492622X-RAY DIFFRACTION100
2.98-3.020.32631370.32242608X-RAY DIFFRACTION100
3.02-3.060.37031380.30642615X-RAY DIFFRACTION100
3.06-3.110.35571370.29172611X-RAY DIFFRACTION100
3.11-3.150.31371370.27522599X-RAY DIFFRACTION100
3.15-3.20.30821380.28172630X-RAY DIFFRACTION100
3.2-3.250.31331380.27872608X-RAY DIFFRACTION100
3.25-3.310.3141380.26962622X-RAY DIFFRACTION100
3.31-3.370.3231380.2822640X-RAY DIFFRACTION100
3.37-3.440.33271380.28162618X-RAY DIFFRACTION100
3.44-3.510.30711380.26832626X-RAY DIFFRACTION100
3.51-3.580.25791390.25432624X-RAY DIFFRACTION100
3.58-3.670.26991380.23582635X-RAY DIFFRACTION100
3.67-3.760.26871390.22642642X-RAY DIFFRACTION100
3.76-3.860.28321400.22722654X-RAY DIFFRACTION100
3.86-3.970.27241390.23332635X-RAY DIFFRACTION100
3.97-4.10.27661390.22512646X-RAY DIFFRACTION100
4.1-4.250.22411400.21262652X-RAY DIFFRACTION100
4.25-4.420.22671400.19482668X-RAY DIFFRACTION99.96
4.42-4.620.21071400.19022658X-RAY DIFFRACTION99.89
4.62-4.860.22631400.19832667X-RAY DIFFRACTION99.86
4.86-5.160.27721410.20872684X-RAY DIFFRACTION99.89
5.16-5.560.26191420.21852685X-RAY DIFFRACTION99.93
5.56-6.120.28481430.2322716X-RAY DIFFRACTION99.97
6.12-70.29141440.23392737X-RAY DIFFRACTION99.93
7-8.810.2281460.19532773X-RAY DIFFRACTION99.97
8.81-46.10.18991550.1932945X-RAY DIFFRACTION99.17

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