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- PDB-3psb: Furo[2,3-c]pyridine-based Indanone Oximes as Potent and Selective... -

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Basic information

Entry
Database: PDB / ID: 3psb
TitleFuro[2,3-c]pyridine-based Indanone Oximes as Potent and Selective B-Raf Inhibitors
ComponentsB-RAF PROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / ATP-binding / Cardiomyopathy / Disease mutation / Metal-binding / Nucleotide-binding / Phorbol-ester binding / Phosphoprotein / Proto-oncogene / Serine/threonine-protein kinase / Zinc-finger / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / thyroid gland development / MAP kinase kinase activity / 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 / protein kinase activity / neuron projection / 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-SM6 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.4 Å
AuthorsMorales, T. / Vigers, G.P.A. / Brandhuber, B.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: The Discovery of furo[2,3-c]pyridine-based indanone oximes as potent and selective B-Raf inhibitors.
Authors: Buckmelter, A.J. / Ren, L. / Laird, E.R. / Rast, B. / Miknis, G. / Wenglowsky, S. / Schlachter, S. / Welch, M. / Tarlton, E. / Grina, J. / Lyssikatos, J. / Brandhuber, B.J. / Morales, T. / ...Authors: Buckmelter, A.J. / Ren, L. / Laird, E.R. / Rast, B. / Miknis, G. / Wenglowsky, S. / Schlachter, S. / Welch, M. / Tarlton, E. / Grina, J. / Lyssikatos, J. / Brandhuber, B.J. / Morales, T. / Randolph, N. / Vigers, G. / Martinson, M. / Callejo, M.
History
DepositionDec 1, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 19, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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

Downloads & links

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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)71,1704
Polymers70,4352
Non-polymers7352
Water0
1
A: B-RAF PROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5852
Polymers35,2181
Non-polymers3671
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: B-RAF PROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5852
Polymers35,2181
Non-polymers3671
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.073, 101.073, 162.952
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: 35217.633 Da / Num. of mol.: 2 / Fragment: UNP residues 432-726
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-SM6 / ethyl 3-{[1-(hydroxyamino)-2H-inden-5-yl]amino}thieno[2,3-c]pyridine-2-carboxylate


Mass: 367.422 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H17N3O3S

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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: 2.95 Å3/Da / Density % sol: 58.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 10% PEG 8K 100mM Hepes pH8.0 3% aminocaproic acid 10% glycerol 2.6mg/ml protein 500uM inhibitor, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Apr 29, 2005
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3.4→30 Å / Num. all: 12196 / Num. obs: 12160 / % possible obs: 99.7 % / Observed criterion σ(I): 0 / Redundancy: 14.1 % / Rmerge(I) obs: 0.17 / Rsym value: 0.17 / Net I/σ(I): 6.12
Reflection shellResolution: 3.4→3.6 Å / Redundancy: 14.5 % / Rmerge(I) obs: 0.395 / Mean I/σ(I) obs: 2 / Num. unique all: 1727 / Rsym value: 0.381 / % possible all: 99.7

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3D4Q

3d4q


Resolution: 3.4→28.63 Å / Cor.coef. Fo:Fc: 0.897 / Cor.coef. Fo:Fc free: 0.871 / SU B: 25.508 / SU ML: 0.411 / Cross valid method: THROUGHOUT / ESU R Free: 0.564 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2681 621 5.1 %RANDOM
Rwork0.22445 ---
obs0.22671 11511 100 %-
all-12196 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 45.714 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å20 Å20 Å2
2--0.04 Å20 Å2
3----0.09 Å2
Refinement stepCycle: LAST / Resolution: 3.4→28.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4200 0 52 0 4252
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0224350
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1361.9785877
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4685522
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.53223.871186
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.12515793
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1981526
X-RAY DIFFRACTIONr_chiral_restr0.0750.2645
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213248
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3891.52616
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.71324236
X-RAY DIFFRACTIONr_scbond_it0.51831734
X-RAY DIFFRACTIONr_scangle_it0.9434.51641
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.4→3.487 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.32 43 -
Rwork0.264 832 -
obs--100 %

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