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- PDB-4dbn: Crystal Structure of the Kinase domain of Human B-raf with a [1,3... -

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Basic information

Entry
Database: PDB / ID: 4dbn
TitleCrystal Structure of the Kinase domain of Human B-raf with a [1,3]thiazolo[5,4-b]pyridine derivative
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase drug complex / Ser/Thr Kinase / ATP Binding / Phosphorylation / 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 / 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-0JA / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3.15 Å
AuthorsYano, J.K. / Aertgeerts, K.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds.
Authors: Okaniwa, M. / Hirose, M. / Imada, T. / Ohashi, T. / Hayashi, Y. / Miyazaki, T. / Arita, T. / Yabuki, M. / Kakoi, K. / Kato, J. / Takagi, T. / Kawamoto, T. / Yao, S. / Sumita, A. / Tsutsumi, ...Authors: Okaniwa, M. / Hirose, M. / Imada, T. / Ohashi, T. / Hayashi, Y. / Miyazaki, T. / Arita, T. / Yabuki, M. / Kakoi, K. / Kato, J. / Takagi, T. / Kawamoto, T. / Yao, S. / Sumita, A. / Tsutsumi, S. / Tottori, T. / Oki, H. / Sang, B.C. / Yano, J. / Aertgeerts, K. / Yoshida, S. / Ishikawa, T.
History
DepositionJan 16, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 11, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 13, 2012Group: Database references
Revision 1.2Feb 28, 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)65,7414
Polymers64,6452
Non-polymers1,0962
Water73941
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)32,8702
Polymers32,3221
Non-polymers5481
Water181
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)32,8702
Polymers32,3221
Non-polymers5481
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)111.040, 111.040, 146.844
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: 32322.379 Da / Num. of mol.: 2 / Fragment: Kinase Domain (UNP residues 445-726)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, P94, RAFB1 / Plasmid: pFASTBAC / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-0JA / 2-chloro-3-(1-cyanocyclopropyl)-N-[5-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]benzamide


Mass: 547.988 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H19ClFN5O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 41 / 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: 3.5 Å3/Da / Density % sol: 64.87 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.3
Details: 9.6% PEG 8000, 0.8M LiCl, 100 mM Tris, pH 8.3, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 92 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 11, 2009
RadiationMonochromator: Double crystal cryo-cooled Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.15→30 Å / Num. all: 16557 / Num. obs: 16557 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0

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Processing

Software
NameVersionClassificationNB
REFMACrefinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 3.15→30 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.889 / WRfactor Rfree: 0.2095 / WRfactor Rwork: 0.1662 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8332 / SU B: 39.69 / SU ML: 0.307 / SU R Cruickshank DPI: 0.3517 / SU Rfree: 0.4088 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.409 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2434 825 5 %RANDOM
Rwork0.196 ---
obs0.1984 16557 99.55 %-
all-16424 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 115.76 Å2 / Biso mean: 46.1384 Å2 / Biso min: 15.86 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å20 Å20 Å2
2---0.38 Å20 Å2
3---0.75 Å2
Refinement stepCycle: LAST / Resolution: 3.15→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4153 0 76 41 4270
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0224328
X-RAY DIFFRACTIONr_bond_other_d0.0010.022937
X-RAY DIFFRACTIONr_angle_refined_deg1.1321.9815855
X-RAY DIFFRACTIONr_angle_other_deg0.78337162
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9155516
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.78623.797187
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.53615778
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9871527
X-RAY DIFFRACTIONr_chiral_restr0.1750.2639
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214714
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02846
X-RAY DIFFRACTIONr_mcbond_it0.2331.52582
X-RAY DIFFRACTIONr_mcbond_other0.031.51052
X-RAY DIFFRACTIONr_mcangle_it0.45424174
X-RAY DIFFRACTIONr_scbond_it0.61531746
X-RAY DIFFRACTIONr_scangle_it1.0974.51669
LS refinement shellResolution: 3.148→3.229 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 49 -
Rwork0.285 1117 -
all-1166 -
obs--98.73 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.1466-0.24050.5874.30380.8047.8830.0473-0.6054-0.04510.64090.0544-0.87510.3730.9198-0.10170.240.0489-0.0090.22920.02340.300348.64-31.139613.8098
21.113-1.5605-1.61985.45291.51873.10620.15150.19990.0106-0.3553-0.0425-0.016-0.2285-0.07-0.1090.187-0.00340.0590.1855-0.03430.116243.5362-43.6015-9.0645
31.88790.0101-0.55994.4742-0.51088.65810.04060.33610.5317-0.6904-0.1072-0.1516-0.6861-0.13930.06660.30380.08490.06120.11540.06710.261536.1387-12.8069-2.5515
45.3059-2.1218-2.10563.06492.06152.56670.03780.1987-0.10660.0794-0.0060.1859-0.0022-0.1282-0.03190.0792-0.02540.03090.06940.02730.082620.7864-15.604118.5082
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A447 - 532
2X-RAY DIFFRACTION2A533 - 720
3X-RAY DIFFRACTION2A901
4X-RAY DIFFRACTION3B447 - 532
5X-RAY DIFFRACTION4B533 - 719
6X-RAY DIFFRACTION4B901

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