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- PDB-6p3d: The co-crystal structure of BRAF(V600E) with ponatinib -

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Basic information

Entry
Database: PDB / ID: 6p3d
TitleThe co-crystal structure of BRAF(V600E) with ponatinib
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / inhibitor / cancer / melanoma / TRANSFERASE-TRANSFERASE INHIBITOR complex / ONCOPROTEIN
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 / 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 / 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 / cell body / positive regulation of peptidyl-serine phosphorylation / T cell differentiation in thymus / 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 / 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
Similarity search - Domain/homology
Chem-0LI / AMMONIUM ION / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 Å
AuthorsAgianian, B. / Gavathiotis, E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R01CA178394 United States
Citation
#1: Journal: Cancer Cell / Year: 2016
Title: An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling.
Authors: Karoulia, Z. / Wu, Y. / Ahmed, T.A. / Xin, Q. / Bollard, J. / Krepler, C. / Wu, X. / Zhang, C. / Bollag, G. / Herlyn, M. / Fagin, J.A. / Lujambio, A. / Gavathiotis, E. / Poulikakos, P.I.
History
DepositionMay 23, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 23, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,19613
Polymers33,7531
Non-polymers1,44312
Water1,74797
1
A: Serine/threonine-protein kinase B-raf
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)70,39226
Polymers67,5052
Non-polymers2,88624
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z+1/41
Buried area6490 Å2
ΔGint-212 kcal/mol
Surface area23760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.839, 118.839, 51.530
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number95
Space group name H-MP4322
Components on special symmetry positions
IDModelComponents
11A-1136-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Serine/threonine-protein kinase B-raf / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 33752.668 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN RESIDUES 448-721
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Plasmid: MODIFIED PET28 / Production host: Escherichia coli (E. coli) / Variant (production host): BL21-CODON PLUS(DE3)-RIPL
References: UniProt: P15056, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 109 molecules

#2: Chemical ChemComp-0LI / 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide / Ponatinib / Ponatinib


Mass: 532.559 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H27F3N6O / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-NH4 / AMMONIUM ION / Ammonium


Mass: 18.038 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: H4N
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 97 / 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: 2.7 Å3/Da / Density % sol: 54.36 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 2 M AMMONIUM SULFATE, 5% (V/V) 2 -PROPANOL, PH 7.5, VAPOR DIFFUSION, SITTING DROP, TEMPERATURE 291K
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.03324 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 7, 2016
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03324 Å / Relative weight: 1
ReflectionResolution: 2.105→118.839 Å / Num. obs: 21866 / % possible obs: 99.5 % / Redundancy: 8.1 % / Rsym value: 0.101 / Net I/σ(I): 13.6
Reflection shellResolution: 2.11→2.22 Å / Redundancy: 8.3 % / Rmerge(I) obs: 0.403 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 3097 / Rsym value: 0.403 / % possible all: 98.4

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Processing

Software
NameVersionClassification
iMOSFLM7.2.1data reduction
SCALA3.3.22data scaling
PHASER2.7.17phasing
REFMAC5.8.0158refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.11→84.03 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.919 / SU B: 4.571 / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.177 / ESU R Free: 0.175 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.245 1117 5.1 %RANDOM
Rwork0.185 ---
obs0.188 20746 99.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 32.77 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å20 Å20 Å2
2--0.15 Å20 Å2
3----0.29 Å2
Refinement stepCycle: LAST / Resolution: 2.11→84.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2108 0 88 97 2293
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0192231
X-RAY DIFFRACTIONr_bond_other_d0.0020.022067
X-RAY DIFFRACTIONr_angle_refined_deg1.9631.9973008
X-RAY DIFFRACTIONr_angle_other_deg1.03334797
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9465262
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.8223.77698
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.27515403
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.5141516
X-RAY DIFFRACTIONr_chiral_restr0.1030.2327
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212383
X-RAY DIFFRACTIONr_gen_planes_other0.0070.02445
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.11→2.16 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.28 79 -
Rwork0.249 1474 -
obs--96.4 %

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