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- PDB-4xv9: B-Raf Kinase domain in complex with PLX5568 -

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Basic information

Entry
Database: PDB / ID: 4xv9
TitleB-Raf Kinase domain in complex with PLX5568
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / B-RAF / BRAF / PROTO-ONCOGENE / V600E / KINASE / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


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 / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...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 / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / negative regulation of fibroblast migration / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / positive regulation of axonogenesis / regulation of T cell differentiation / mitogen-activated protein kinase kinase binding / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / positive regulation of axon regeneration / stress fiber assembly / face development / MAP kinase kinase activity / synaptic vesicle exocytosis / thyroid gland development / somatic stem cell population maintenance / MAP kinase kinase kinase activity / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / response to cAMP / positive regulation of peptidyl-serine phosphorylation / positive regulation of stress fiber assembly / positive regulation of substrate adhesion-dependent cell spreading / ERK1 and ERK2 cascade / substrate adhesion-dependent cell spreading / cellular response to calcium ion / thymus development / animal organ morphogenesis / RAF activation / cellular response to nerve growth factor stimulus / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / response to peptide hormone / centriolar satellite / long-term synaptic potentiation / epidermal growth factor receptor signaling pathway / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / MAPK cascade / cellular response to xenobiotic stimulus / presynapse / T cell receptor signaling pathway / regulation of cell population proliferation / T cell differentiation in thymus / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / postsynapse / protein kinase activity / neuron projection / ciliary basal body / cilium / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / calcium ion binding / positive regulation of gene expression / protein-containing complex binding / negative regulation of apoptotic process / glutamatergic synapse / mitochondrion / zinc ion binding
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-1OO / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
Authorszhang, Y. / zhang, c. / wang, w.
CitationJournal: Nature / Year: 2015
Title: RAF inhibitors that evade paradoxical MAPK pathway activation.
Authors: Zhang, C. / Spevak, W. / Zhang, Y. / Burton, E.A. / Ma, Y. / Habets, G. / Zhang, J. / Lin, J. / Ewing, T. / Matusow, B. / Tsang, G. / Marimuthu, A. / Cho, H. / Wu, G. / Wang, W. / Fong, D. / ...Authors: Zhang, C. / Spevak, W. / Zhang, Y. / Burton, E.A. / Ma, Y. / Habets, G. / Zhang, J. / Lin, J. / Ewing, T. / Matusow, B. / Tsang, G. / Marimuthu, A. / Cho, H. / Wu, G. / Wang, W. / Fong, D. / Nguyen, H. / Shi, S. / Womack, P. / Nespi, M. / Shellooe, R. / Carias, H. / Powell, B. / Light, E. / Sanftner, L. / Walters, J. / Tsai, J. / West, B.L. / Visor, G. / Rezaei, H. / Lin, P.S. / Nolop, K. / Ibrahim, P.N. / Hirth, P. / Bollag, G.
History
DepositionJan 26, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 28, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2015Group: 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 / citation / database_2 / diffrn_radiation_wavelength / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)33,9073
Polymers33,2951
Non-polymers6122
Water4,522251
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)67,8146
Polymers66,5902
Non-polymers1,2244
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_664-y+1,-x+1,-z-1/41
Unit cell
Length a, b, c (Å)119.297, 119.297, 52.507
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number95
Space group name H-MP4322

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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: 33295.152 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 444-705
Mutation: I543A,I544S,I551K,Q562R,L588N,K630S,F667E,Y673S,A688R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Escherichia coli (E. coli)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-1OO / N-{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl}-4-(trifluoromethyl)benzenesulfonamide


Mass: 515.840 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H11ClF5N3O3S
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 251 / 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: 2.81 Å3/Da / Density % sol: 56.16 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1M MES AT PH6.0, 35% (V/V) 2-METHYL- 2,4-PENTANEDIOL 0.2M LI2SO4, VAPOR DIFFUSION, SITTING DROP, TEMPERATURE 277K
PH range: 6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 21, 2006
RadiationMonochromator: SIDE-SCATTERING CUBEROOT I-BEAM BENT SINGLE CRYSTAL,ASYMETRIC CUT 12.2 DEGS.
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2→119.523 Å / Num. obs: 26185 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 13.6 % / Net I/σ(I): 6.9
Reflection shellResolution: 2→2.05 Å / % possible all: 100

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
REFMAC5.1.25refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→18.63 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.921 / SU B: 4.107 / SU ML: 0.115 / Cross valid method: THROUGHOUT / ESU R: 0.167 / ESU R Free: 0.151 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.238 1266 4.8 %RANDOM
Rwork0.205 ---
obs0.206 24901 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 27.42 Å2
Baniso -1Baniso -2Baniso -3
1-0.26 Å20 Å20 Å2
2--0.26 Å20 Å2
3----0.51 Å2
Refinement stepCycle: LAST / Resolution: 2→18.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2079 0 39 251 2369
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0212224
X-RAY DIFFRACTIONr_bond_other_d0.0020.022000
X-RAY DIFFRACTIONr_angle_refined_deg1.1441.9733016
X-RAY DIFFRACTIONr_angle_other_deg0.75834666
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0085273
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0590.2323
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022476
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02456
X-RAY DIFFRACTIONr_nbd_refined0.1720.2472
X-RAY DIFFRACTIONr_nbd_other0.2050.22361
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.080.21245
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1190.2173
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1130.216
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2270.254
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0780.228
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.1991.51339
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.37922169
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.6253885
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.0264.5847
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→2.05 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.245 92
Rwork0.223 1804
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)
10.85150.7170.11182.3533-1.02842.2046-0.0368-0.0313-0.0705-0.0230.01370.0503-0.060.01270.0230.1461-0.00010.00190.1468-0.01550.147980.41521.0414.446
20.98550.3691-0.21571.447-1.05732.5082-0.01830.1147-0.1627-0.05130.09280.15690.208-0.1813-0.07450.0448-0.00090.0390.0011-0.0090.098477.6120.2480.782
31.16440.27790.19090.6992-0.1742.5131-0.01130.1447-0.0565-0.0267-0.01210.10060.1915-0.14120.02330.1394-0.01180.02860.1403-0.00430.243379.3622.5073.183
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1136 - 1151
2X-RAY DIFFRACTION2A448 - 466
3X-RAY DIFFRACTION2A467 - 484
4X-RAY DIFFRACTION2A485 - 534
5X-RAY DIFFRACTION2A535 - 582
6X-RAY DIFFRACTION2A583 - 587
7X-RAY DIFFRACTION2A588 - 597
8X-RAY DIFFRACTION2A613 - 667
9X-RAY DIFFRACTION2A668 - 705
10X-RAY DIFFRACTION2A706 - 721
11X-RAY DIFFRACTION2A801
12X-RAY DIFFRACTION2A802
13X-RAY DIFFRACTION2A901 - 1070
14X-RAY DIFFRACTION3A1071 - 1135

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