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- PDB-3ppj: Human B-Raf Kinase in Complex with a Furopyridine Inhibitor -

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Basic information

Entry
Database: PDB / ID: 3ppj
TitleHuman B-Raf Kinase in Complex with a Furopyridine Inhibitor
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Protein kinase / ATP-competitive inhibitor / 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 / 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 / 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-FOI / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.7 Å
AuthorsVoegtli, W.C. / Vigers, G.P.A. / Morales, T. / Brandhuber, B.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Non-oxime inhibitors of B-Raf(V600E) kinase.
Authors: Ren, L. / Wenglowsky, S. / Miknis, G. / Rast, B. / Buckmelter, A.J. / Ely, R.J. / Schlachter, S. / Laird, E.R. / Randolph, N. / Callejo, M. / Martinson, M. / Galbraith, S. / Brandhuber, B.J. ...Authors: Ren, L. / Wenglowsky, S. / Miknis, G. / Rast, B. / Buckmelter, A.J. / Ely, R.J. / Schlachter, S. / Laird, E.R. / Randolph, N. / Callejo, M. / Martinson, M. / Galbraith, S. / Brandhuber, B.J. / Vigers, G. / Morales, T. / Voegtli, W.C. / Lyssikatos, J.
History
DepositionNov 24, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 2, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 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

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)71,1104
Polymers70,4352
Non-polymers6752
Water0
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5552
Polymers35,2181
Non-polymers3371
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5552
Polymers35,2181
Non-polymers3371
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)100.540, 100.540, 162.110
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 Serine/threonine-protein kinase B-raf / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 35217.633 Da / Num. of mol.: 2 / Fragment: Kinase domain, UNP residues 432-726
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Plasmid: pBac4x-1 / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): Hi5
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-FOI / methyl 3-{[(5S)-1-(hydroxyamino)-5H-inden-5-yl]amino}furo[2,3-c]pyridine-2-carboxylate / (E)-methyl 3-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-ylamino)furo[2,3-c]pyridine-2-carboxylate


Mass: 337.329 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15N3O4

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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: 2.91 Å3/Da / Density % sol: 57.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: PEG 3350, pH 7.0, 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: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 15, 2005
RadiationMonochromator: Confocal optic / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 3.7→30 Å / Num. all: 9357 / Num. obs: 9357 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 3.7→3.93 Å / Num. unique all: 1403 / % possible all: 100

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Processing

Software
NameVersionClassification
CrystalCleardata collection
CNSrefinement
CNX2005refinement
MOSFLMdata reduction
SCALAdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.7→27.48 Å / Rfactor Rfree error: 0.012 / Data cutoff high absF: 4870847.72 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.272 502 5.4 %RANDOM
Rwork0.25 ---
obs0.251 9357 100 %-
all-9357 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 30.5524 Å2 / ksol: 0.336907 e/Å3
Displacement parametersBiso mean: 40.6 Å2
Baniso -1Baniso -2Baniso -3
1--1.73 Å20 Å20 Å2
2---1.73 Å20 Å2
3---3.46 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.44 Å0.38 Å
Luzzati d res low-5 Å
Luzzati sigma a0.48 Å0.34 Å
Refinement stepCycle: LAST / Resolution: 3.7→27.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4200 0 50 0 4250
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.1
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.3
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.58
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.331.5
X-RAY DIFFRACTIONc_mcangle_it2.452
X-RAY DIFFRACTIONc_scbond_it1.282
X-RAY DIFFRACTIONc_scangle_it2.282.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 3.7→3.93 Å / Rfactor Rfree error: 0.027 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.261 95 6.3 %
Rwork0.26 1409 -
obs--100 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paprotein.top
X-RAY DIFFRACTION2AR00428097.parAR00428097.top
X-RAY DIFFRACTION3water_rep.parawater.top

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