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- PDB-4fc0: Crystal Structure of Human Kinase Domain of B-raf with a DFG-out ... -

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Basic information

Entry
Database: PDB / ID: 4fc0
TitleCrystal Structure of Human Kinase Domain of B-raf with a DFG-out Inhibitor
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


CD4-positive, alpha-beta T cell differentiation / trehalose metabolism in response to stress / 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 / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...CD4-positive, alpha-beta T cell differentiation / trehalose metabolism in response to stress / 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 / 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 / cellular response to calcium ion / ERK1 and ERK2 cascade / substrate adhesion-dependent cell spreading / cellular response to nerve growth factor stimulus / thymus development / long-term synaptic potentiation / animal organ morphogenesis / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / 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 receptor signaling pathway / regulation of cell population proliferation / cell body / T cell differentiation in thymus / scaffold protein binding / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / protein kinase activity / neuron projection / protein phosphorylation / intracellular membrane-bounded organelle / protein serine kinase activity / 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-0T2 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.95 Å
AuthorsYano, J.K. / Aertgeerts, K.
CitationJournal: Bioorg.Med.Chem. / Year: 2012
Title: Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives.
Authors: Hirose, M. / Okaniwa, M. / Miyazaki, T. / Imada, T. / Ohashi, T. / Tanaka, Y. / Arita, T. / Yabuki, M. / Kawamoto, T. / Tsutsumi, S. / Sumita, A. / Takagi, T. / Sang, B.C. / Yano, J. / ...Authors: Hirose, M. / Okaniwa, M. / Miyazaki, T. / Imada, T. / Ohashi, T. / Tanaka, Y. / Arita, T. / Yabuki, M. / Kawamoto, T. / Tsutsumi, S. / Sumita, A. / Takagi, T. / Sang, B.C. / Yano, J. / Aertgeerts, K. / Yoshida, S. / Ishikawa, T.
History
DepositionMay 23, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 8, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 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)65,8034
Polymers64,6452
Non-polymers1,1582
Water2,882160
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2340 Å2
ΔGint-4 kcal/mol
Surface area23540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.968, 109.968, 145.973
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, V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1
Plasmid: pFASTBAC / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-0T2 / 2-chloro-3-[(2-cyanopropan-2-yl)oxy]-N-{5-[{2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}(methyl)amino]-2-fluorophenyl}benzamide


Mass: 579.045 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H24ClFN6O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 160 / 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: 3.41 Å3/Da / Density % sol: 63.96 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.3
Details: 7.8% PEG 8000, 0.8M LiCl, 100 mM Tris, pH 8.3, VAPOR DIFFUSION, SITTING DROP, 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: Oct 10, 2008
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: 2.95→40 Å / Num. all: 20800 / Num. obs: 19439 / % possible obs: 99.3 % / Observed criterion σ(F): 1.8 / Observed criterion σ(I): 1.8 / Redundancy: 4.8 % / Rsym value: 0.186

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Processing

Software
NameVersionClassificationNB
REFMACrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.95→30 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.889 / WRfactor Rfree: 0.211 / WRfactor Rwork: 0.1666 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8357 / SU B: 30.277 / SU ML: 0.262 / SU R Cruickshank DPI: 1.3051 / SU Rfree: 0.3564 / Cross valid method: THROUGHOUT / σ(F): 1.8 / ESU R: 1.305 / ESU R Free: 0.356 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2431 986 5.1 %RANDOM
Rwork0.1976 ---
obs0.1999 19355 99.44 %-
all-19355 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 92.06 Å2 / Biso mean: 34.0008 Å2 / Biso min: 10.23 Å2
Baniso -1Baniso -2Baniso -3
1-0.75 Å20 Å20 Å2
2--0.75 Å20 Å2
3----1.5 Å2
Refinement stepCycle: LAST / Resolution: 2.95→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4126 0 80 160 4366
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0224303
X-RAY DIFFRACTIONr_bond_other_d0.0010.022919
X-RAY DIFFRACTIONr_angle_refined_deg1.0791.9825821
X-RAY DIFFRACTIONr_angle_other_deg0.79537116
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5195512
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.21523.73185
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.57315769
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.7041527
X-RAY DIFFRACTIONr_chiral_restr0.0590.2633
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214687
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02841
X-RAY DIFFRACTIONr_mcbond_it0.2421.52567
X-RAY DIFFRACTIONr_mcbond_other0.0341.51045
X-RAY DIFFRACTIONr_mcangle_it0.48224150
X-RAY DIFFRACTIONr_scbond_it0.74831736
X-RAY DIFFRACTIONr_scangle_it1.3174.51665
LS refinement shellResolution: 2.95→3.026 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.345 77 -
Rwork0.315 1288 -
all-1365 -
obs--98.56 %
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)
14.5825-0.5454-1.42073.3343-0.2686.8415-0.1024-0.70830.10130.479-0.0112-0.76680.23480.75760.11360.23430.0357-0.02860.16480.00960.222648.384-30.66313.501
21.0853-0.8051-1.33724.22790.87981.96980.21720.290.0164-0.332-0.12680.1223-0.2539-0.17-0.09040.16520.0274-0.00050.2032-0.02520.05243.538-42.978-9.6
32.3434-0.2855-0.85765.4005-0.2566.24820.05210.51360.546-0.50720.0099-0.341-0.5585-0.1042-0.0620.25610.07280.04510.21520.07940.182836.026-11.988-2.764
44.5082-2.0373-1.55893.22991.82452.4075-0.00260.1944-0.03080.11910.05020.13970.1236-0.0414-0.04760.1256-0.04560.02920.07870.01670.03520.766-15.40618.945
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A447 - 532
2X-RAY DIFFRACTION2A533 - 721
3X-RAY DIFFRACTION3B447 - 532
4X-RAY DIFFRACTION4B533 - 719

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