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- PDB-8f7o: BRAF kinase in complex with TAK580 (tovorafenib) -

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Basic information

Entry
Database: PDB / ID: 8f7o
TitleBRAF kinase in complex with TAK580 (tovorafenib)
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/INHIBITOR / BRAF / TAK580 / tovorafenib / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / head morphogenesis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / head morphogenesis / Signalling to p38 via RIT and RIN / 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 / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / visual learning / MAP2K and MAPK activation / 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 differentiation in thymus / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / 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 / 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
Similarity search - Domain/homology
Chem-QOP / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.54 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)65,0424
Polymers64,0292
Non-polymers1,0132
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.918, 121.998, 57.797
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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-QOP / 6-amino-5-chloro-N-[(1R)-1-(5-{[5-chloro-4-(trifluoromethyl)pyridin-2-yl]carbamoyl}-1,3-thiazol-2-yl)ethyl]pyrimidine-4-carboxamide / tovorafenib


Mass: 506.289 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H12Cl2F3N7O2S / Feature type: SUBJECT OF INVESTIGATION
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: 2.32 Å3/Da / Density % sol: 47.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 8% tacimate pH 8.0, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9786 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 16, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 3.43→200 Å / Num. obs: 8092 / % possible obs: 95.9 % / Redundancy: 12.5 % / CC1/2: 0.968 / Rmerge(I) obs: 0.468 / Rrim(I) all: 0.489 / Net I/σ(I): 3.79
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
3.43-3.642.19110800.472.2831
3.64-3.891.44812560.7091.5081
3.89-4.210.98111650.761.0231
4.21-4.610.68610640.8630.7161
4.61-5.150.5839520.8830.6091
5.15-5.940.5118710.9410.5331
5.94-7.270.3567560.980.3721
7.27-10.270.2335740.9650.2451
10.27-2000.2323740.9660.2431

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Processing

Software
NameVersionClassification
XDSdata scaling
PHENIX1.2refinement
XDSdata reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.54→70.79 Å / SU ML: 0.46 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2693 752 10 %
Rwork0.2151 --
obs0.2207 7519 94.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.54→70.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4195 0 64 0 4259
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024359
X-RAY DIFFRACTIONf_angle_d0.4965882
X-RAY DIFFRACTIONf_dihedral_angle_d11.9531640
X-RAY DIFFRACTIONf_chiral_restr0.042634
X-RAY DIFFRACTIONf_plane_restr0.003752
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.54-3.810.3141500.27641357X-RAY DIFFRACTION97
3.81-4.190.29811480.24071335X-RAY DIFFRACTION96
4.19-4.80.25391470.2021321X-RAY DIFFRACTION93
4.8-6.040.29391510.22011353X-RAY DIFFRACTION95
6.05-70.790.23451560.18591401X-RAY DIFFRACTION92
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)
10.7851-0.1590.20562.80220.84292.54920.21840.64680.1062-0.8853-0.1723-0.2878-0.4288-0.4405-0.12011.07670.05430.0480.79730.20560.7820.117236.9587-5.01
21.21080.91840.87573.5371-0.22243.1941-0.05270.54540.91260.6090.2158-0.22480.23070.3276-0.11640.85650.12620.09980.8370.07520.883824.385334.72953.2733
33.0398-0.8321-0.64392.8138-0.0212.87230.17150.3493-0.01420.20470.02090.34860.2374-0.0463-0.11260.83040.0812-0.04060.6845-0.01330.78899.972230.494114.404
42.5595-3.0402-0.51713.60650.80763.68160.1993-0.94361.21490.81030.04210.1087-0.5696-0.2034-0.14991.0123-0.01260.09930.96610.02321.120215.257339.206924.9299
52.6552-0.1717-1.06773.9248-0.23152.94050.2434-0.22131.14220.6507-0.00250.1187-0.4686-0.4013-0.14431.04640.12770.22360.83320.03630.87156.231336.947830.1235
62.60540.4719-1.40474.19-0.73491.55580.5993-0.0305-1.09361.95640.3048-0.79970.3817-0.5107-0.06960.76090.1831-0.13611.2644-0.02161.250713.457318.455426.7068
71.2185-0.20340.55646.1562-0.80612.5705-0.1333-0.8107-0.44531.14450.6155-1.06150.28490.0626-0.06541.52070.2558-0.12560.8277-0.03190.591429.19279.830816.0283
84.8022-2.9556-0.75522.5512.46025.4333-1.012-1.4349-0.23131.15730.5161-2.20591.03230.2747-0.2491.13210.3639-0.06570.85430.07871.570432.10549.866114.6863
93.07970.6982-0.54830.58271.09163.569-0.2587-0.37890.0643-0.6506-0.1819-1.6331-0.0205-0.25380.15920.46640.1934-0.0331.4968-0.15681.438739.168713.11794.3439
100.3362-0.55520.76193.27120.45981.9746-0.5579-0.64450.10680.47570.38070.3466-0.2181-0.4936-0.07770.78670.02830.12180.86980.15240.699321.36210.19324.6002
114.02140.27771.37183.17280.98753.5852-0.0889-0.3012-0.033-0.12970.3901-0.02910.35320.1413-0.05341.04570.04430.21390.7756-0.03150.784921.559811.8359-4.268
125.2971-2.7819-0.73752.06980.22790.20980.593-0.96990.62020.1654-0.9295-0.04710.3161-0.17650.02850.79030.0174-0.12680.8254-0.10991.061350.56422.4629-12.4902
132.7701-0.2484-0.47032.68530.59791.52190.4030.0462-0.2872-0.7575-0.3466-0.1915-0.01180.4898-0.12041.05820.00690.13150.89690.01110.9622.9985-1.5229-14.4124
141.59780.48051.62662.83480.19141.58450.75170.9040.8606-1.0633-0.58970.3656-0.0957-0.0304-0.06391.1674-0.0380.13350.9512-0.04580.962317.42559.3326-20.1059
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 449 through 491 )
2X-RAY DIFFRACTION2chain 'A' and (resid 492 through 533 )
3X-RAY DIFFRACTION3chain 'A' and (resid 534 through 619 )
4X-RAY DIFFRACTION4chain 'A' and (resid 620 through 651 )
5X-RAY DIFFRACTION5chain 'A' and (resid 652 through 706 )
6X-RAY DIFFRACTION6chain 'A' and (resid 707 through 723 )
7X-RAY DIFFRACTION7chain 'B' and (resid 449 through 475 )
8X-RAY DIFFRACTION8chain 'B' and (resid 476 through 491 )
9X-RAY DIFFRACTION9chain 'B' and (resid 492 through 507 )
10X-RAY DIFFRACTION10chain 'B' and (resid 508 through 549 )
11X-RAY DIFFRACTION11chain 'B' and (resid 550 through 611 )
12X-RAY DIFFRACTION12chain 'B' and (resid 612 through 634 )
13X-RAY DIFFRACTION13chain 'B' and (resid 635 through 670 )
14X-RAY DIFFRACTION14chain 'B' and (resid 671 through 722 )

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