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- PDB-5hi2: BRAF Kinase domain b3aC loop deletion mutant in complex with sorafenib -

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Basic information

Entry
Database: PDB / ID: 5hi2
TitleBRAF Kinase domain b3aC loop deletion mutant in complex with sorafenib
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / 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 / negative regulation of endothelial cell apoptotic process / postsynaptic modulation of chemical synaptic transmission / 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 / RAF activation / Spry regulation of FGF signaling / 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 / MAPK cascade / T cell receptor signaling pathway / presynapse / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / protein phosphorylation / positive regulation of ERK1 and ERK2 cascade / 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 / cytosol / cytoplasm
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-BAX / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.512 Å
AuthorsWhalen, D.M. / Foster, S.A. / Ozen, A. / Wongchenko, M. / Yin, J. / Schaefer, G. / Mayfield, J. / Chmielecki, J. / Stephens, P. / Albacker, L. ...Whalen, D.M. / Foster, S.A. / Ozen, A. / Wongchenko, M. / Yin, J. / Schaefer, G. / Mayfield, J. / Chmielecki, J. / Stephens, P. / Albacker, L. / Yan, Y. / Song, K. / Hatzivassiliou, G. / Eigenbrot, C. / Yu, C. / Shaw, A.S. / Manning, G. / Skelton, N.J. / Hymowitz, S.G. / Malek, S.
CitationJournal: Cancer Cell / Year: 2016
Title: Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.
Authors: Foster, S.A. / Whalen, D.M. / Ozen, A. / Wongchenko, M.J. / Yin, J. / Yen, I. / Schaefer, G. / Mayfield, J.D. / Chmielecki, J. / Stephens, P.J. / Albacker, L.A. / Yan, Y. / Song, K. / ...Authors: Foster, S.A. / Whalen, D.M. / Ozen, A. / Wongchenko, M.J. / Yin, J. / Yen, I. / Schaefer, G. / Mayfield, J.D. / Chmielecki, J. / Stephens, P.J. / Albacker, L.A. / Yan, Y. / Song, K. / Hatzivassiliou, G. / Eigenbrot, C. / Yu, C. / Shaw, A.S. / Manning, G. / Skelton, N.J. / Hymowitz, S.G. / Malek, S.
History
DepositionJan 11, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 20, 2016Group: Database references
Revision 1.2Aug 3, 2016Group: Structure summary
Revision 1.3Sep 27, 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 / pdbx_struct_oper_list
Item: _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)32,8242
Polymers32,3591
Non-polymers4651
Water52229
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area990 Å2
ΔGint-6 kcal/mol
Surface area12420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.625, 114.920, 101.544
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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: 32359.061 Da / Num. of mol.: 1
Mutation: I543A, I544S, I551K, Q562R, L588N, K630S, F667E, Y673S, A688R, L706S, Q709R, S713E, L716E, S720E, P722S, K723G. delta N486-P490
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-BAX / 4-{4-[({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE / Sorafenib


Mass: 464.825 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16ClF3N4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / 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: 2.24 Å3/Da / Density % sol: 45.02 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 6.8 / Details: 20% PEG 3350, and 0.2M Potassium Nitrate

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9537 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 22, 2015
RadiationMonochromator: Liquid nitrogen-cooled double crystal, non fixed exit slit. Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.51→45.56 Å / Num. obs: 10142 / % possible obs: 98.9 % / Redundancy: 6.61 % / Rsym value: 0.131 / Net I/σ(I): 12.49
Reflection shellResolution: 2.51→2.64 Å / Mean I/σ(I) obs: 2.18 / % possible all: 98.7

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MNE chain B

4mne


Resolution: 2.512→45.559 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 27.03
RfactorNum. reflection% reflection
Rfree0.2371 1009 9.96 %
Rwork0.1851 --
obs0.1905 10133 98.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.512→45.559 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1989 0 32 29 2050
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092063
X-RAY DIFFRACTIONf_angle_d1.1882777
X-RAY DIFFRACTIONf_dihedral_angle_d15.127780
X-RAY DIFFRACTIONf_chiral_restr0.077297
X-RAY DIFFRACTIONf_plane_restr0.004353
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5121-2.64460.34841380.26791266X-RAY DIFFRACTION98
2.6446-2.81020.33861430.24671285X-RAY DIFFRACTION99
2.8102-3.02720.34141420.24351277X-RAY DIFFRACTION99
3.0272-3.33170.26181450.20461303X-RAY DIFFRACTION99
3.3317-3.81360.2261450.18141301X-RAY DIFFRACTION99
3.8136-4.80390.19491440.14531322X-RAY DIFFRACTION99
4.8039-45.56620.19861520.1691370X-RAY DIFFRACTION98
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)
13.8289-1.1651-0.68381.84210.94132.7054-0.0101-0.23410.06690.14020.008-0.24650.31120.21080.00250.2208-0.00370.00980.38410.0340.131230.621215.0864-14.8374
23.1088-0.2572-0.98253.09560.69524.4041-0.2869-0.2321-0.00110.33750.03460.18350.0852-0.32470.2150.2169-0.01650.04910.3645-0.04860.219412.365919.9774-5.1395
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 456 through 560 )
2X-RAY DIFFRACTION2chain 'A' and (resid 561 through 721 )

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