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- PDB-4ksp: Crystal Structure of Human B-raf bound to a DFG-out Inhibitor TAK-632 -

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Basic information

Entry
Database: PDB / ID: 4ksp
TitleCrystal Structure of Human B-raf bound to a DFG-out Inhibitor TAK-632
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / human serine/theronine protein Kinase / kinase drug complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of axon regeneration / 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 / ARMS-mediated activation / endothelial cell apoptotic process / myeloid progenitor cell differentiation / SHOC2 M1731 mutant abolishes MRAS complex function ...positive regulation of axon regeneration / 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 / ARMS-mediated activation / endothelial cell apoptotic process / myeloid progenitor cell differentiation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of D-glucose transmembrane transport / negative regulation of fibroblast migration / establishment of protein localization to membrane / positive regulation of axonogenesis / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / stress fiber assembly / face development / MAP kinase kinase activity / thyroid gland development / synaptic vesicle exocytosis / somatic stem cell population maintenance / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / positive regulation of stress fiber assembly / ERK1 and ERK2 cascade / positive regulation of substrate adhesion-dependent cell spreading / substrate adhesion-dependent cell spreading / cellular response to calcium ion / thymus development / animal organ morphogenesis / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / centriolar satellite / cellular response to xenobiotic stimulus / epidermal growth factor receptor signaling pathway / long-term synaptic potentiation / 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 / Signaling by BRAF and RAF1 fusions / T cell differentiation in thymus / T cell receptor signaling pathway / presynapse / MAPK cascade / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / postsynapse / neuron projection / cilium / ciliary basal body / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / calcium ion binding / positive regulation of gene expression / negative regulation of apoptotic process / glutamatergic synapse / mitochondrion / zinc ion binding / ATP binding / identical protein binding / nucleus / plasma membrane / cytoplasm / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-1SU / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.93 Å
AuthorsYano, J.K. / Masanori, O.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of C-7-Substituted 1,3-Benzothiazole Derivatives.
Authors: Okaniwa, M. / Hirose, M. / Arita, T. / Yabuki, M. / Nakamura, A. / Takagi, T. / Kawamoto, T. / Uchiyama, N. / Sumita, A. / Tsutsumi, S. / Tottori, T. / Inui, Y. / Sang, B.C. / Yano, J. / ...Authors: Okaniwa, M. / Hirose, M. / Arita, T. / Yabuki, M. / Nakamura, A. / Takagi, T. / Kawamoto, T. / Uchiyama, N. / Sumita, A. / Tsutsumi, S. / Tottori, T. / Inui, Y. / Sang, B.C. / Yano, J. / Aertgeerts, K. / Yoshida, S. / Ishikawa, T.
History
DepositionMay 17, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 24, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Sep 20, 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

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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)65,7544
Polymers64,6452
Non-polymers1,1092
Water70339
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)32,8772
Polymers32,3221
Non-polymers5551
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)32,8772
Polymers32,3221
Non-polymers5551
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)111.495, 111.495, 145.487
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: UNP residues 445-726
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: BRAF, BRAF1, P94, RAFB1, V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1
Plasmid: pFASTBAC / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-1SU / N-{7-cyano-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide


Mass: 554.515 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H18F4N4O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 64.83 %
Crystal growTemperature: 277 K / Method: sitting drop, vapor diffusion / pH: 8.3
Details: 9.6 % PEG 8000, 0.8M LiCl, 100 mM Tris pH 8.3, sitting drop, vapor diffusion, temperature 277K

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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: Jun 13, 2010
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: 2.93→50 Å / Num. all: 20307 / Num. obs: 20267 / % possible obs: 99.8 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.157 / Χ2: 1.104 / Net I/σ(I): 5.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.93-33.90.8619600.971198.5
3-3.064.50.8299980.777199.8
3.06-3.115.20.78810000.9641100
3.11-3.185.80.7659901.2241100
3.18-3.256.30.6689861.1051100
3.25-3.326.70.5669920.9371100
3.32-3.417.10.47610021.0121100
3.41-3.57.30.429951.1761100
3.5-3.67.50.37410000.9871100
3.6-3.727.50.29310041.0871100
3.72-3.857.50.24610091.169199.9
3.85-47.50.2039951.167199.9
4-4.197.40.17210111.1931100
4.19-4.417.30.14810131.24199.7
4.41-4.687.20.1310141.286199.8
4.68-5.047.10.12810201.2551100
5.04-5.557.20.11910301.15199.9
5.55-6.357.30.11410401.0921100
6.35-870.08510671.042199.9
8-506.30.05811410.972199.4

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMAC5.7.0029refinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
DENZOdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DBN

4dbn


Resolution: 2.93→35 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.917 / Occupancy max: 1 / Occupancy min: 1 / SU B: 29.092 / SU ML: 0.261 / Cross valid method: THROUGHOUT / ESU R: 0.807 / ESU R Free: 0.34 / Stereochemistry target values: Engh & Huber
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2417 1031 5.1 %RANDOM
Rwork0.1941 ---
obs0.1965 20089 98.4 %-
all-20307 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 166.3 Å2 / Biso mean: 79.5058 Å2 / Biso min: 29.33 Å2
Baniso -1Baniso -2Baniso -3
1--0.89 Å2-0 Å2-0 Å2
2---0.89 Å2-0 Å2
3---1.77 Å2
Refinement stepCycle: LAST / Resolution: 2.93→35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4099 0 78 39 4216
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0194274
X-RAY DIFFRACTIONr_bond_other_d0.0020.024139
X-RAY DIFFRACTIONr_angle_refined_deg1.3171.9825780
X-RAY DIFFRACTIONr_angle_other_deg0.73439512
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8965509
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.82523.871186
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.1715766
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1881526
X-RAY DIFFRACTIONr_chiral_restr0.0660.2625
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214838
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021006
LS refinement shellResolution: 2.93→3.003 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.479 62 -
Rwork0.302 1218 -
all-1280 -
obs--87.31 %
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)
18.6934-0.25723.391211.6401-3.22379.34520.1778-0.9883-0.57250.1873-0.2353-1.25510.84060.10770.05750.35840.05830.02480.31590.05030.382846.6073-33.662617.7393
21.46050.572-0.10126.47472.08833.27360.045-0.2468-0.02910.2438-0.1161-0.5593-0.02260.22950.07120.11580.04330.09740.13610.06980.261244.3592-34.95435.1776
35.5404-1.77351.53488.47511.86493.01520.1903-0.40710.02350.12270.0289-0.1364-0.32120.3082-0.21920.3157-0.05350.06650.1597-0.03730.027544.3852-37.2362-1.1347
45.9221-2.0268-2.40787.35282.40953.92520.0587-0.19440.25380.18010.1795-0.6627-0.2990.6059-0.23820.2042-0.02210.03060.1256-0.02260.100249.2665-42.7441-7.9571
53.7362-0.8302-1.49134.66291.02272.67140.03460.323-0.3296-0.2863-0.12450.158-0.0442-0.17410.08990.1332-0.00110.01140.1144-0.06080.069747.2332-55.6821-11.8917
63.588-0.14331.99626.9011-0.0544.97580.46660.8520.0935-0.8448-0.29560.8491-0.4632-0.481-0.1710.55790.1858-0.00210.51550.02790.15440.2625-39.868-19.0557
75.35560.09560.16198.8544-0.45465.6361-0.19870.11521.0791-0.89540.060.5302-0.8953-0.47670.13870.60410.1797-0.08070.24780.05480.488534.1333-12.513-7.414
85.093-0.7997-1.33981.61260.22593.2904-0.04980.43720.6337-0.3927-0.0225-0.1162-0.2656-0.17750.07240.3220.0791-0.07360.0989-0.03070.310331.1752-15.59863.3498
96.1643-0.4992-0.65495.63391.53172.88890.21810.3554-0.3890.07530.0126-0.15380.18890.0156-0.23070.12320.00560.02420.1472-0.08270.125627.2736-21.464313.3768
108.4977-3.3049-0.57286.74213.94717.58280.27710.95191.5559-0.72530.2859-0.8588-1.2390.8558-0.56290.3497-0.04920.15420.31690.08040.367123.8859-4.022816.8797
114.8271-1.2378-0.88513.9192.10882.95790.03270.1038-0.26430.2253-0.01020.20960.1585-0.2519-0.02250.1698-0.04720.07120.0830.01150.068413.9834-11.877121.0743
129.4412-2.4898-1.68336.16660.23775.3668-0.0108-0.726-0.85671.37550.1534-0.020.86520.1228-0.14260.53650.0057-0.07080.30190.05020.182623.9988-20.130428.2847
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A447 - 474
2X-RAY DIFFRACTION2A475 - 568
3X-RAY DIFFRACTION3A569 - 586
4X-RAY DIFFRACTION4A587 - 650
5X-RAY DIFFRACTION5A651 - 685
6X-RAY DIFFRACTION6A686 - 721
7X-RAY DIFFRACTION7B447 - 490
8X-RAY DIFFRACTION8B491 - 548
9X-RAY DIFFRACTION9B549 - 591
10X-RAY DIFFRACTION10B592 - 633
11X-RAY DIFFRACTION11B634 - 685
12X-RAY DIFFRACTION12B686 - 719

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