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- PDB-6xfp: Crystal Structure of BRAF kinase domain bound to Belvarafenib -

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Basic information

Entry
Database: PDB / ID: 6xfp
TitleCrystal Structure of BRAF kinase domain bound to Belvarafenib
ComponentsSerine/threonine-protein kinase B-raf
KeywordsSIGNALING PROTEIN / BRAF Belvarafenib
Function / homology
Function and homology information


non-specific serine/threonine protein kinase / positive regulation of protein phosphorylation / protein phosphorylation / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / negative regulation of apoptotic process / signal transduction / ATP binding / 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-V1Y / non-specific serine/threonine protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsYin, J. / Sudhamsu, J.
CitationJournal: Nature / Year: 2021
Title: ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.
Authors: Yen, I. / Shanahan, F. / Lee, J. / Hong, Y.S. / Shin, S.J. / Moore, A.R. / Sudhamsu, J. / Chang, M.T. / Bae, I. / Dela Cruz, D. / Hunsaker, T. / Klijn, C. / Liau, N.P.D. / Lin, E. / Martin, ...Authors: Yen, I. / Shanahan, F. / Lee, J. / Hong, Y.S. / Shin, S.J. / Moore, A.R. / Sudhamsu, J. / Chang, M.T. / Bae, I. / Dela Cruz, D. / Hunsaker, T. / Klijn, C. / Liau, N.P.D. / Lin, E. / Martin, S.E. / Modrusan, Z. / Piskol, R. / Segal, E. / Venkatanarayan, A. / Ye, X. / Yin, J. / Zhang, L. / Kim, J.S. / Lim, H.S. / Kim, K.P. / Kim, Y.J. / Han, H.S. / Lee, S.J. / Kim, S.T. / Jung, M. / Hong, Y.H. / Noh, Y.S. / Choi, M. / Han, O. / Nowicka, M. / Srinivasan, S. / Yan, Y. / Kim, T.W. / Malek, S.
History
DepositionJun 16, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 10, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 9, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 30, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)33,5248
Polymers32,8331
Non-polymers6927
Water1,54986
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)67,04916
Polymers65,6652
Non-polymers1,38314
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y,-z+1/21
Buried area3810 Å2
ΔGint-124 kcal/mol
Surface area23580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.793, 119.563, 103.934
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-804-

CL

21A-920-

HOH

31A-980-

HOH

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Components

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


Mass: 32832.621 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF / Production host: Escherichia coli (E. coli) / References: UniProt: H7C560
#2: Chemical ChemComp-V1Y / 4-amino-N-{1-[(3-chloro-2-fluorophenyl)amino]-6-methylisoquinolin-5-yl}thieno[3,2-d]pyrimidine-7-carboxamide / Belvarafenib / Belvarafenib


Mass: 478.929 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H16ClFN6OS / Comment: antitumor, inhibitor*YM
#3: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 86 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.31 Å3/Da / Density % sol: 46.72 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: (18% PEG 3350, and 0.2M Na Iodine, and 0.1 M bis-Tris propane pH6.5)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9742 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9742 Å / Relative weight: 1
ReflectionResolution: 2→59.782 Å / Num. obs: 20506 / % possible obs: 95.62 % / Redundancy: 5.9 % / Biso Wilson estimate: 32.24 Å2 / CC1/2: 0.999 / Net I/σ(I): 12.64
Reflection shellResolution: 2→2.07 Å / Num. unique obs: 1961 / CC1/2: 0.636

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHASERphasing
PHENIX1.12-2829_finalrefinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MNF

4mnf


Resolution: 2→59.782 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 29.68 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2568 1233 6.15 %
Rwork0.2039 18823 -
obs0.2072 20056 95.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 93.84 Å2 / Biso mean: 39.9297 Å2 / Biso min: 13.02 Å2
Refinement stepCycle: final / Resolution: 2→59.782 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2178 0 39 86 2303
Biso mean--29.27 38.93 -
Num. residues----272
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082296
X-RAY DIFFRACTIONf_angle_d0.9423105
X-RAY DIFFRACTIONf_chiral_restr0.054329
X-RAY DIFFRACTIONf_plane_restr0.006400
X-RAY DIFFRACTIONf_dihedral_angle_d8.7121927
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2-2.08010.37151090.3056165977
2.0801-2.17480.34531420.26192150100
2.1748-2.28950.30591220.2627188787
2.2895-2.43290.29331410.22142156100
2.4329-2.62070.32261420.21212166100
2.6207-2.88450.28071420.20372169100
2.8845-3.30180.24441430.19862187100
3.3018-4.15980.22281410.1742213696
4.1598-100.22541510.19372313100

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