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- PDB-6v34: Crystal structure of BRAF V600E oncogenic mutant in complex with ... -

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Basic information

Entry
Database: PDB / ID: 6v34
TitleCrystal structure of BRAF V600E oncogenic mutant in complex with TAK-580
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE / BRAF
Function / homology
Function and homology information


regulation of intracellular signal transduction / Signalling to p38 via RIT and RIN / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / MAP kinase kinase activity ...regulation of intracellular signal transduction / Signalling to p38 via RIT and RIN / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / MAP kinase kinase activity / intracellular membrane-bounded organelle / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / postsynaptic modulation of chemical synaptic transmission / animal organ morphogenesis / cellular response to calcium ion / protein modification process / RAF activation / Signaling by high-kinase activity BRAF mutants / Spry regulation of FGF signaling / MAP2K and MAPK activation / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling 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 / Negative regulation of MAPK pathway / Signaling by BRAF and RAF1 fusions / cell body / scaffold protein binding / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / protein phosphorylation / non-specific serine/threonine protein kinase / postsynapse / neuron projection / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of gene expression / calcium ion binding / negative regulation of apoptotic process / glutamatergic synapse / signal transduction / mitochondrion / zinc ion binding / ATP binding / metal ion 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. ...: / 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 / 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-QOP / non-specific serine/threonine protein kinase / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.15 Å
AuthorsGonzalez Del-Pino, G. / Li, K. / Eck, M.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P50 CA165962 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 CA242461 United States
CitationJournal: To Be Published
Title: Crystal structure of BRAF V600E oncogenic mutant in complex with TAK-580
Authors: Gonzalez Del-Pino, G. / Li, K. / Eck, M.J.
History
DepositionNov 25, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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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)65,1024
Polymers64,0892
Non-polymers1,0132
Water00
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5512
Polymers32,0451
Non-polymers5061
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5512
Polymers32,0451
Non-polymers5061
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.802, 85.244, 122.905
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Serine/threonine-protein kinase B-raf


Mass: 32044.666 Da / Num. of mol.: 2
Mutation: I543A, I544S, I551K, Q562R, L588N, K630S, F667E, Y673S, A688R, L706S, Q709R, S713E, L716E, S720E, P722S, K723A, V600E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 pLysS / References: UniProt: A0A2R8Y8E0, UniProt: P15056*PLUS
#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 / Comment: medication, inhibitor*YM
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: 1.99 Å3/Da / Density % sol: 38.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.2 M Sodium Acetate, 0.1 M Tris: HCl, pH 8.5, 30 % (w/v) PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.15→24.925 Å / Num. obs: 9189 / % possible obs: 96.7 % / Redundancy: 6.1 % / Biso Wilson estimate: 73.37 Å2 / CC1/2: 0.989 / Rmerge(I) obs: 0.2515 / Rpim(I) all: 0.1126 / Rrim(I) all: 0.2675 / Net I/σ(I): 7.56
Reflection shellResolution: 3.15→3.263 Å / Mean I/σ(I) obs: 1.55 / Num. unique obs: 893 / CC1/2: 0.708 / Rpim(I) all: 0.6916

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5ITA

5ita


Resolution: 3.15→24.92 Å / SU ML: 0.53 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 31.53 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2859 481 5.32 %
Rwork0.2549 8565 -
obs0.2566 9046 96.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 202.39 Å2 / Biso mean: 81.5009 Å2 / Biso min: 42.4 Å2
Refinement stepCycle: final / Resolution: 3.15→24.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4023 0 64 0 4087
Biso mean--66.9 --
Num. residues----503
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 3

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.15-3.260.34251500.33172821297198
3.61-4.540.33861530.27532755290894
4.54-24.920.23651780.21252989316798
Refinement TLS params.Method: refined / Origin x: 2.9358 Å / Origin y: -13.9754 Å / Origin z: 27.1289 Å
111213212223313233
T0.4206 Å20.078 Å2-0.0031 Å2-0.4438 Å2-0.0683 Å2--0.6581 Å2
L2.5038 °20.416 °20.8624 °2-1.0695 °20.5296 °2--4.9826 °2
S0.0202 Å °-0.3337 Å °-0.2765 Å °0.1127 Å °0.0599 Å °-0.02 Å °0.1923 Å °0.2538 Å °-0.0617 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA449 - 723
2X-RAY DIFFRACTION1allA801
3X-RAY DIFFRACTION1allB449 - 721
4X-RAY DIFFRACTION1allB801

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