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- PDB-2fb8: Structure of the B-Raf kinase domain bound to SB-590885 -

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Basic information

Entry
Database: PDB / ID: 2fb8
TitleStructure of the B-Raf kinase domain bound to SB-590885
ComponentsB-Raf proto-oncogene serine/threonine-protein kinase
KeywordsTRANSFERASE / kinase domain
Function / homology
Function and homology information


trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / head morphogenesis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / head morphogenesis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / positive regulation of axonogenesis / Frs2-mediated activation / stress fiber assembly / positive regulation of axon regeneration / face development / synaptic vesicle exocytosis / somatic stem cell population maintenance / MAP kinase kinase activity / thyroid gland development / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / response to cAMP / positive regulation of stress fiber assembly / ERK1 and ERK2 cascade / cellular response to calcium ion / substrate adhesion-dependent cell spreading / cellular response to nerve growth factor stimulus / thymus development / long-term synaptic potentiation / animal organ morphogenesis / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / visual learning / MAP2K and MAPK activation / epidermal growth factor receptor signaling pathway / 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 / MAPK cascade / Signaling by BRAF and RAF1 fusions / cellular response to xenobiotic stimulus / presynapse / positive regulation of peptidyl-serine phosphorylation / T cell differentiation in thymus / cell body / regulation of cell population proliferation / T cell receptor signaling pathway / scaffold protein binding / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / neuron projection / protein kinase activity / protein phosphorylation / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / calcium ion binding / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / mitochondrion / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol
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. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain ...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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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-215 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsLougheed, J.C. / Lee, J. / Chau, D.C. / Stout, T.J.
CitationJournal: Cancer Res. / Year: 2006
Title: Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885.
Authors: King, A.J. / Patrick, D.R. / Batorsky, R.S. / Ho, M.L. / Do, H.T. / Zhang, S.Y. / Kumar, R. / Rusnak, D.W. / Takle, A.K. / Wilson, D.M. / Hugger, E. / Wang, L. / Karreth, F. / Lougheed, J.C. ...Authors: King, A.J. / Patrick, D.R. / Batorsky, R.S. / Ho, M.L. / Do, H.T. / Zhang, S.Y. / Kumar, R. / Rusnak, D.W. / Takle, A.K. / Wilson, D.M. / Hugger, E. / Wang, L. / Karreth, F. / Lougheed, J.C. / Lee, J. / Chau, D. / Stout, T.J. / May, E.W. / Rominger, C.M. / Schaber, M.D. / Luo, L. / Lakdawala, A.S. / Adams, J.L. / Contractor, R.G. / Smalley, K.S. / Herlyn, M. / Morrissey, M.M. / Tuveson, D.A. / Huang, P.S.
History
DepositionDec 8, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 12, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 14, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: B-Raf proto-oncogene serine/threonine-protein kinase
B: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7354
Polymers63,8282
Non-polymers9072
Water64936
1
A: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3672
Polymers31,9141
Non-polymers4541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3672
Polymers31,9141
Non-polymers4541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)95.638, 95.638, 159.222
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein B-Raf proto-oncogene serine/threonine-protein kinase / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 31913.881 Da / Num. of mol.: 2 / Fragment: B-Raf kinase domain, residues 445-723
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Plasmid: pACGP67 / Cell line (production host): Sf-9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P15056, EC: 2.7.1.37
#2: Chemical ChemComp-215 / (1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-IMIDAZOL-4-YL)INDAN-1-ONE OXIME


Mass: 453.536 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H27N5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 36 / Source method: isolated from a natural source / Formula: H2O

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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: 2.85 Å3/Da / Density % sol: 56.86 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 8% PEG 8000, 0.4 M LiCl, 0.1 M Tris, 0.02 M Bis-Tris Propane, 15% glycerol, 1 mM DTT, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 18K, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 13, 2005
RadiationMonochromator: Si / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.9→46.42 Å / Num. all: 16843 / Num. obs: 16667 / % possible obs: 98.4 % / Redundancy: 6 % / Rmerge(I) obs: 0.227 / Rsym value: 0.227 / Net I/σ(I): 2.5
Reflection shellResolution: 2.9→3.06 Å / Redundancy: 6.2 % / Rmerge(I) obs: 0.489 / Mean I/σ(I) obs: 1.5 / Num. unique all: 2360 / Rsym value: 0.489 / % possible all: 98.4

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Phasing

Phasing MRRfactor: 0.448 / Cor.coef. Fo:Fc: 0.455
Highest resolutionLowest resolution
Rotation3 Å46.41 Å
Translation3 Å46.41 Å

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Processing

Software
NameVersionClassificationNB
SCALAdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT1.701data extraction
MOSFLMdata reduction
CCP4(SCALA)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→46.42 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.797 / SU B: 17.667 / SU ML: 0.338 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.448 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.291 840 5 %RANDOM
Rwork0.199 ---
all0.203 16653 --
obs0.203 16653 97.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.017 Å2
Baniso -1Baniso -2Baniso -3
1--0.39 Å20 Å20 Å2
2---0.39 Å20 Å2
3---0.77 Å2
Refinement stepCycle: LAST / Resolution: 2.9→46.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4134 0 68 36 4238
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0224298
X-RAY DIFFRACTIONr_angle_refined_deg2.2191.9785804
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.5575514
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.73123.804184
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.26615778
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.6581526
X-RAY DIFFRACTIONr_chiral_restr0.130.2636
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023192
X-RAY DIFFRACTIONr_nbd_refined0.2760.22266
X-RAY DIFFRACTIONr_nbtor_refined0.3420.22913
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1840.2195
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.230.250
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1460.24
X-RAY DIFFRACTIONr_mcbond_it0.8881.52643
X-RAY DIFFRACTIONr_mcangle_it1.59524162
X-RAY DIFFRACTIONr_scbond_it1.94731897
X-RAY DIFFRACTIONr_scangle_it3.1324.51642
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 74 -
Rwork0.242 1104 -
obs-1178 97.84 %

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