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- PDB-3q96: B-Raf kinase domain in complex with a tetrahydronaphthalene inhibitor -

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Basic information

Entry
Database: PDB / ID: 3q96
TitleB-Raf kinase domain in complex with a tetrahydronaphthalene inhibitor
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Design / Optimization / Potent / Orally Bioavailable / Tetrahydronaphthalene / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / Signalling to p38 via RIT and RIN / head morphogenesis / 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 ...CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / Signalling to p38 via RIT and RIN / head morphogenesis / 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 D-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 / MAP kinase kinase activity / synaptic vesicle exocytosis / somatic stem cell population maintenance / thyroid gland development / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of stress fiber assembly / response to cAMP / ERK1 and ERK2 cascade / cellular response to calcium ion / substrate adhesion-dependent cell spreading / cellular response to nerve growth factor stimulus / thymus development / animal organ morphogenesis / long-term synaptic potentiation / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / epidermal growth factor receptor signaling pathway / visual learning / 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 / positive regulation of peptidyl-serine phosphorylation / presynapse / T cell receptor signaling pathway / regulation of cell population proliferation / T cell differentiation in thymus / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / protein kinase activity / neuron projection / protein phosphorylation / intracellular membrane-bounded organelle / protein serine kinase activity / protein serine/threonine kinase activity / calcium ion binding / positive regulation of gene expression / protein-containing complex binding / 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) ...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 / 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-0NF / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsSintchak, M.D. / Aertgeerts, K. / Yano, J.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Design and optimization of potent and orally bioavailable tetrahydronaphthalene raf inhibitors.
Authors: Gould, A.E. / Adams, R. / Adhikari, S. / Aertgeerts, K. / Afroze, R. / Blackburn, C. / Calderwood, E.F. / Chau, R. / Chouitar, J. / Duffey, M.O. / England, D.B. / Farrer, C. / Forsyth, N. / ...Authors: Gould, A.E. / Adams, R. / Adhikari, S. / Aertgeerts, K. / Afroze, R. / Blackburn, C. / Calderwood, E.F. / Chau, R. / Chouitar, J. / Duffey, M.O. / England, D.B. / Farrer, C. / Forsyth, N. / Garcia, K. / Gaulin, J. / Greenspan, P.D. / Guo, R. / Harrison, S.J. / Huang, S.C. / Iartchouk, N. / Janowick, D. / Kim, M.S. / Kulkarni, B. / Langston, S.P. / Liu, J.X. / Ma, L.T. / Menon, S. / Mizutani, H. / Paske, E. / Renou, C.C. / Rezaei, M. / Rowland, R.S. / Sintchak, M.D. / Smith, M.D. / Stroud, S.G. / Tregay, M. / Tian, Y. / Veiby, O.P. / Vos, T.J. / Vyskocil, S. / Williams, J. / Xu, T. / Yang, J.J. / Yano, J. / Zeng, H. / Zhang, D.M. / Zhang, Q. / Galvin, K.M.
History
DepositionJan 7, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase B-raf
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,3784
Polymers64,3002
Non-polymers1,0772
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6892
Polymers32,1501
Non-polymers5391
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6892
Polymers32,1501
Non-polymers5391
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)94.029, 94.029, 165.264
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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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: 32150.240 Da / Num. of mol.: 2 / Fragment: residues 446-727
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-0NF / (2S)-N-[3-(2-aminopropan-2-yl)-5-(trifluoromethyl)phenyl]-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide


Mass: 538.561 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H29F3N4O3

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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: 2.84 Å3/Da / Density % sol: 56.7 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: 14.025% PEG 8000, 0.8M NP Lithium Cl, 0.06M Tris base, 0.04M Tris Cl, VAPOR DIFFUSION, temperature 298K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.1→81.73 Å / Num. obs: 14022 / % possible obs: 100 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.206 / Χ2: 1.004 / Net I/σ(I): 4.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
3.1-3.156.60.6666810.981100
3.15-3.216.70.5656801.014100
3.21-3.276.60.5476731.01100
3.27-3.346.60.4526941.017100
3.34-3.416.70.4196810.985100
3.41-3.496.60.3466861.002100
3.49-3.586.70.3216831.011100
3.58-3.686.60.2596850.991100
3.68-3.786.70.2416891.025100
3.78-3.916.50.1997000.991100
3.91-4.046.60.1746890.991100
4.04-4.216.60.1656820.97899.9
4.21-4.46.50.1516981.014100
4.4-4.636.50.1417011.011100
4.63-4.926.40.1397061.005100
4.92-5.36.40.1567131.046100
5.3-5.836.30.177101.008100
5.83-6.676.10.1537191.022100
6.67-8.46.10.097410.967100
8.4-505.70.0518111.00399.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.5.0109refinement
PDB_EXTRACT3.1data extraction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.1→81.73 Å / Cor.coef. Fo:Fc: 0.897 / Cor.coef. Fo:Fc free: 0.835 / Occupancy max: 1 / Occupancy min: 1 / SU B: 21.366 / SU ML: 0.376 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.536 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS; U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2878 1381 10 %RANDOM
Rwork0.2271 ---
obs0.2332 13851 98.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 61.34 Å2 / Biso mean: 30.4413 Å2 / Biso min: 15.56 Å2
Baniso -1Baniso -2Baniso -3
1-0.95 Å20 Å20 Å2
2--0.95 Å20 Å2
3----1.91 Å2
Refinement stepCycle: LAST / Resolution: 3.1→81.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4075 0 78 0 4153
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0224250
X-RAY DIFFRACTIONr_angle_refined_deg1.0831.9815760
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0235510
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.60723.785177
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.51515745
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5931524
X-RAY DIFFRACTIONr_chiral_restr0.0690.2637
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213153
X-RAY DIFFRACTIONr_mcbond_it0.4031.52558
X-RAY DIFFRACTIONr_mcangle_it0.74724129
X-RAY DIFFRACTIONr_scbond_it0.6631692
X-RAY DIFFRACTIONr_scangle_it1.1854.51631
LS refinement shellResolution: 3.101→3.182 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.33 90 -
Rwork0.254 831 -
all-921 -
obs--90.03 %

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