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- PDB-8jnb: CRAF ras-binding domain chimera, ligand complex -

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Basic information

Entry
Database: PDB / ID: 8jnb
TitleCRAF ras-binding domain chimera, ligand complex
ComponentsRAF proto-oncogene serine/threonine-protein kinase, CRaf
KeywordsSIGNALING PROTEIN / raf / craf / chimera / beta-grasp
Function / homology
Function and homology information


death-inducing signaling complex assembly / intermediate filament cytoskeleton organization / CD4-positive, alpha-beta T cell differentiation / regulation of Rho protein signal transduction / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / myeloid progenitor cell differentiation / negative regulation of synaptic vesicle exocytosis / type B pancreatic cell proliferation / Signalling to p38 via RIT and RIN / head morphogenesis ...death-inducing signaling complex assembly / intermediate filament cytoskeleton organization / CD4-positive, alpha-beta T cell differentiation / regulation of Rho protein signal transduction / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / myeloid progenitor cell differentiation / negative regulation of synaptic vesicle exocytosis / type B pancreatic cell proliferation / Signalling to p38 via RIT and RIN / head morphogenesis / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / Rap1 signalling / regulation of cell motility / negative regulation of fibroblast migration / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / insulin secretion involved in cellular response to glucose stimulus / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / positive regulation of axonogenesis / GP1b-IX-V activation signalling / activation of adenylate cyclase activity / IFNG signaling activates MAPKs / Frs2-mediated activation / stress fiber assembly / regulation of cell differentiation / ERBB2-ERBB3 signaling pathway / positive regulation of axon regeneration / pseudopodium / face development / somatic stem cell population maintenance / MAP kinase kinase activity / synaptic vesicle exocytosis / neurotrophin TRK receptor signaling pathway / thyroid gland development / extrinsic apoptotic signaling pathway via death domain receptors / MAP kinase kinase kinase activity / type II interferon-mediated signaling pathway / negative regulation of protein-containing complex assembly / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of endothelial cell apoptotic process / Schwann cell development / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of stress fiber assembly / response to cAMP / response to muscle stretch / myelination / cellular response to calcium ion / ERK1 and ERK2 cascade / CD209 (DC-SIGN) signaling / substrate adhesion-dependent cell spreading / : / insulin-like growth factor receptor signaling pathway / thymus development / cellular response to nerve growth factor stimulus / long-term synaptic potentiation / animal organ morphogenesis / RAF activation / wound healing / Signaling by high-kinase activity BRAF mutants / Spry regulation of FGF signaling / MAP2K and MAPK activation / visual learning / epidermal growth factor receptor signaling pathway / Stimuli-sensing channels / response to peptide hormone / 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 / Signaling by BRAF and RAF1 fusions / MAPK cascade / cellular response to xenobiotic stimulus / insulin receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / presynapse / regulation of cell population proliferation / T cell receptor signaling pathway / T cell differentiation in thymus / cell body / scaffold protein binding / regulation of apoptotic process / negative regulation of neuron apoptotic process / mitochondrial outer membrane / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / protein kinase activity / neuron projection / protein phosphorylation / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / protein serine kinase activity / protein serine/threonine kinase activity / calcium ion binding
Similarity search - Function
Raf-like Ras-binding / Raf-like Ras-binding domain / 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) ...Raf-like Ras-binding / Raf-like Ras-binding domain / 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 / 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
: / RAF proto-oncogene serine/threonine-protein kinase / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsKawamura, T. / Kumasaka, T.
Funding support Japan, 2items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)17nk0101309h0003 Japan
Japan Science and Technology22-20103170 Japan
CitationJournal: To Be Published
Title: Small-molecule RAS/RAF-binding Inhibitors Allosterically Disrupt RAF Conformation and Exert Efficacy Against Broad-spectrum RAS-driven Cancers
Authors: Yoshikawa, Y. / Makino, Y. / Kubota, H. / Kawamura, T. / Matsumoto, S. / Yuki, H. / Shibaike, A. / Okamura, M. / Okada, T. / Kataoka, T. / Honma, T. / Kumasaka, T. / Koyama, H. / Shima, F.
History
DepositionJun 6, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: RAF proto-oncogene serine/threonine-protein kinase, CRaf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)10,8852
Polymers10,5171
Non-polymers3681
Water1,31573
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.019, 69.775, 39.746
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

#1: Protein RAF proto-oncogene serine/threonine-protein kinase, CRaf / Proto-oncogene c-RAF / cRaf / Raf-1 / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral ...Proto-oncogene c-RAF / cRaf / Raf-1 / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 10517.026 Da / Num. of mol.: 1 / Mutation: K65S, F99Y, S120W, D129E
Source method: isolated from a genetically manipulated source
Details: 102-LHEHKGKKARLD-113 replaced with QDGEKKPIG (201-209) from P15056
Source: (gene. exp.) Homo sapiens (human) / Gene: RAF1, RAF, BRAF, BRAF1, RAFB1 / Plasmid: pGEX-6p-1 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P04049, UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-USX / 2-[4-[[(2S)-1-ethanoyl-3-oxidanylidene-2H-indol-2-yl]methyl]-2-methoxy-phenoxy]ethanamide


Mass: 368.383 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N2O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / Source method: isolated from a natural source / Formula: H2O
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: 2.14 Å3/Da / Density % sol: 42.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: 0.5M ammonium sulfate, 1.0M lithium sulfate, 0.1M sodium citrate, pH 5.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL38B1 / Wavelength: 1 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Dec 2, 2017
RadiationMonochromator: SI(111) SILICON CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.62→34.89 Å / Num. obs: 11698 / % possible obs: 98.65 % / Redundancy: 7.1 % / Biso Wilson estimate: 22.51 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.04916 / Rpim(I) all: 0.01983 / Rrim(I) all: 0.0531 / Net I/σ(I): 22.6
Reflection shellResolution: 1.62→1.678 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.8984 / Mean I/σ(I) obs: 2.02 / Num. unique obs: 1097 / CC1/2: 0.95 / Rpim(I) all: 0.3693 / Rrim(I) all: 0.9701 / % possible all: 93.43

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Processing

Software
NameVersionClassification
PHENIX1.17_3644refinement
XDSFeb 3, 2021data reduction
XDSFeb 3, 2021data scaling
PHASER2.8.3phasing
Coot0.8.8model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.62→34.89 Å / SU ML: 0.2092 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.9054
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2422 587 5.02 %
Rwork0.2039 11107 -
obs0.2058 11694 98.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.32 Å2
Refinement stepCycle: LAST / Resolution: 1.62→34.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms635 0 27 73 735
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0113681
X-RAY DIFFRACTIONf_angle_d1.6318930
X-RAY DIFFRACTIONf_chiral_restr0.0788105
X-RAY DIFFRACTIONf_plane_restr0.0065118
X-RAY DIFFRACTIONf_dihedral_angle_d21.3288243
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.62-1.780.31051410.26892670X-RAY DIFFRACTION96.43
1.78-2.040.26511450.21082736X-RAY DIFFRACTION99.17
2.04-2.570.23421460.21952787X-RAY DIFFRACTION99.29
2.57-34.890.23231550.18882914X-RAY DIFFRACTION99.74

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