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- PDB-8f7p: BRAF kinase in complex with LXH254 (naporafenib) -

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Basic information

Entry
Database: PDB / ID: 8f7p
TitleBRAF kinase in complex with LXH254 (naporafenib)
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/INHIBITOR / BRAF / LXH254 / naporafenib / 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 / somatic stem cell population maintenance / thyroid gland development / MAP kinase kinase kinase activity / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / response to cAMP / positive regulation of stress fiber assembly / positive regulation of substrate adhesion-dependent cell spreading / ERK1 and ERK2 cascade / cellular response to calcium ion / substrate adhesion-dependent cell spreading / thymus development / animal organ morphogenesis / long-term synaptic potentiation / RAF activation / Spry regulation of FGF signaling / epidermal growth factor receptor signaling pathway / cellular response to nerve growth factor stimulus / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / positive regulation of peptidyl-serine phosphorylation / visual learning / 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 / T cell receptor signaling pathway / presynapse / T cell differentiation in thymus / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / eukaryotic translation initiation factor 2alpha kinase activity / positive regulation of ERK1 and ERK2 cascade / 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 / non-specific serine/threonine protein kinase / protein kinase activity / postsynapse / neuron projection / protein phosphorylation / intracellular membrane-bounded organelle / protein serine kinase activity / protein serine/threonine kinase activity / calcium ion binding / positive regulation of gene expression / protein-containing complex binding / negative regulation of apoptotic process / glutamatergic synapse / mitochondrion / ATP binding / identical protein binding / nucleus / plasma membrane
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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-K81 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.74 Å
AuthorsTkacik, E. / Li, K. / Gonzalez Del-Pino, G. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R35CA242461 United States
CitationJournal: J.Biol.Chem. / Year: 2023
Title: Structure and RAF family kinase isoform selectivity of type II RAF inhibitors tovorafenib and naporafenib.
Authors: Tkacik, E. / Li, K. / Gonzalez-Del Pino, G. / Ha, B.H. / Vinals, J. / Park, E. / Beyett, T.S. / Eck, M.J.
History
DepositionNov 20, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 12, 2023Provider: repository / Type: Initial release
Revision 1.1May 3, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)65,0344
Polymers64,0292
Non-polymers1,0052
Water41423
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.647, 101.746, 58.688
Angle α, β, γ (deg.)90.00, 109.67, 90.00
Int Tables number4
Space group name H-MP1211

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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: 32014.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-K81 / N-{3-[2-(2-hydroxyethoxy)-6-(morpholin-4-yl)pyridin-4-yl]-4-methylphenyl}-2-(trifluoromethyl)pyridine-4-carboxamide


Mass: 502.486 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H25F3N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.18 Å3/Da / Density % sol: 43.58 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.2 M MgCl2, 0.1 M Tris pH 8.5, 25% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.36→200 Å / Num. obs: 22342 / % possible obs: 98.5 % / Redundancy: 5.8 % / CC1/2: 0.993 / Rmerge(I) obs: 0.226 / Rrim(I) all: 0.248 / Net I/σ(I): 5.48
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.36-2.52.31634010.382.561
2.5-2.681.75834210.6711.9261
2.68-2.891.03131780.8821.1331
2.89-3.160.58429380.9380.6431
3.16-3.540.2926410.9780.3221
3.54-4.080.17323350.9910.191
4.08-4.990.11719930.9910.1291
4.99-7.030.10915480.9910.1211
7.03-2000.0718870.9960.0781

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Processing

Software
NameVersionClassification
XDSdata scaling
PHENIX1.2refinement
XDSdata reduction
PHENIXphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.74→46.75 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.69 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2582 687 4.77 %
Rwork0.2142 --
obs0.2163 14391 99.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.74→46.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4157 0 72 23 4252
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044340
X-RAY DIFFRACTIONf_angle_d0.7585849
X-RAY DIFFRACTIONf_dihedral_angle_d16.4611647
X-RAY DIFFRACTIONf_chiral_restr0.051628
X-RAY DIFFRACTIONf_plane_restr0.005737
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.74-2.950.39781650.30392704X-RAY DIFFRACTION99
2.95-3.250.33591330.25832729X-RAY DIFFRACTION100
3.25-3.720.24321290.21762715X-RAY DIFFRACTION98
3.72-4.680.23381320.1882754X-RAY DIFFRACTION100
4.69-46.750.20891280.19462802X-RAY DIFFRACTION99
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)
1-0.0742-0.01320.06550.1162-0.03080.11730.0990.04720.072-0.42920.07530.16910.07020.219300.3317-0.00050.00120.2405-0.01430.263417.9628-3.768310.2926
20.5698-0.40980.13380.32790.00210.15770.09350.0514-0.086-0.0982-0.10250.0694-0.0689-0.0516-00.2340.00810.03760.24940.02760.192810.6455-3.47226.2643
30.45620.0184-0.2920.01440.3052-0.11010.0306-0.0240.01790.07370.0507-0.01950.0598-0.105500.2895-0.0295-0.00770.26120.01150.2303-1.7384-7.33920.6856
40.6810.01260.47630.2983-0.02780.50710.0302-0.0931-0.1865-0.13670.09270.20450.0956-0.0521-00.2988-0.023-0.02880.26510.03290.3045-12.738-17.085420.1343
50.1144-0.0382-0.03260.08610.22280.13110.06240.09350.4707-0.5910.2390.1680.0058-0.069400.4161-0.0114-0.04260.27160.00710.492-12.206315.43819.6535
60.68250.09450.24880.4788-0.0987-0.14060.00820.0562-0.07160.01780.0151-0.0516-0.0125-0.022300.236-0.0037-0.00960.2687-0.00780.25851.202117.802713.4084
70.2686-0.1701-0.44910.38060.54020.28940.20090.00040.193-0.3995-0.28510.0714-0.39160.2219-00.5210.04270.01320.3587-0.02950.30710.699523.752113.4147
80.5856-0.1464-0.19390.29520.29020.3362-0.1053-0.02060.04-0.01530.0646-0.064-0.1309-0.028800.2998-0.0231-0.03520.22060.00580.262917.659629.620720.1268
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 449 through 475 )
2X-RAY DIFFRACTION2chain 'A' and (resid 476 through 533 )
3X-RAY DIFFRACTION3chain 'A' and (resid 534 through 616 )
4X-RAY DIFFRACTION4chain 'A' and (resid 617 through 721 )
5X-RAY DIFFRACTION5chain 'B' and (resid 448 through 475 )
6X-RAY DIFFRACTION6chain 'B' and (resid 476 through 581 )
7X-RAY DIFFRACTION7chain 'B' and (resid 582 through 613 )
8X-RAY DIFFRACTION8chain 'B' and (resid 614 through 721 )

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