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- PDB-3og7: B-Raf Kinase V600E oncogenic mutant in complex with PLX4032 -

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Basic information

Entry
Database: PDB / ID: 3og7
TitleB-Raf Kinase V600E oncogenic mutant in complex with PLX4032
ComponentsAKAP9-BRAF fusion protein
Keywordstransferase/transferase inhibitor / B-Raf / BRAF / PROTO-ONCOGENE / V600E / Kinase / TRANSFERASE / 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 / microtubule organizing center / 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 / thyroid gland development / MAP kinase kinase activity / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / response to cAMP / positive regulation of stress fiber assembly / ERK1 and ERK2 cascade / cellular response to calcium ion / 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 / cell body / regulation of cell population proliferation / T cell receptor signaling pathway / scaffold protein binding / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / molecular adaptor activity / non-specific serine/threonine protein kinase / protein kinase activity / neuron projection / protein phosphorylation / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / calcium ion binding / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / signal transduction / mitochondrion / DNA binding / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
ELK domain / A-kinase anchor protein 9/Pericentrin / ELK / 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. ...ELK domain / A-kinase anchor protein 9/Pericentrin / ELK / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-032 / Serine/threonine-protein kinase B-raf / AKAP9-BRAF fusion protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsZhang, Y. / Zhang, K.Y. / Zhang, C.
CitationJournal: Nature / Year: 2010
Title: Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.
Authors: Bollag, G. / Hirth, P. / Tsai, J. / Zhang, J. / Ibrahim, P.N. / Cho, H. / Spevak, W. / Zhang, C. / Zhang, Y. / Habets, G. / Burton, E.A. / Wong, B. / Tsang, G. / West, B.L. / Powell, B. / ...Authors: Bollag, G. / Hirth, P. / Tsai, J. / Zhang, J. / Ibrahim, P.N. / Cho, H. / Spevak, W. / Zhang, C. / Zhang, Y. / Habets, G. / Burton, E.A. / Wong, B. / Tsang, G. / West, B.L. / Powell, B. / Shellooe, R. / Marimuthu, A. / Nguyen, H. / Zhang, K.Y. / Artis, D.R. / Schlessinger, J. / Su, F. / Higgins, B. / Iyer, R. / D'Andrea, K. / Koehler, A. / Stumm, M. / Lin, P.S. / Lee, R.J. / Grippo, J. / Puzanov, I. / Kim, K.B. / Ribas, A. / McArthur, G.A. / Sosman, J.A. / Chapman, P.B. / Flaherty, K.T. / Xu, X. / Nathanson, K.L. / Nolop, K.
History
DepositionAug 16, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Structure summary / Item: _chem_comp.pdbx_synonyms
Revision 1.3May 2, 2018Group: Data collection / Structure summary / Category: struct_keywords
Item: _struct_keywords.pdbx_keywords / _struct_keywords.text
Revision 1.4Feb 21, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: AKAP9-BRAF fusion protein
B: AKAP9-BRAF fusion protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,4453
Polymers65,9552
Non-polymers4901
Water1,17165
1
A: AKAP9-BRAF fusion protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4682
Polymers32,9781
Non-polymers4901
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: AKAP9-BRAF fusion protein


Theoretical massNumber of molelcules
Total (without water)32,9781
Polymers32,9781
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.770, 104.424, 110.128
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 AKAP9-BRAF fusion protein / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 32977.742 Da / Num. of mol.: 2 / Fragment: Kinase domain (unp residues 1175-1446)
Mutation: I544A, I551K, Q562R, L588N, K630S, F667E, Y673S, A688R, L706S, A688R, L706S, Q709R, S713E, L716E, S720E
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: Q5IBP5, UniProt: P15056*PLUS, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-032 / N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide / Vemurafenib / PLX4032 / Vemurafenib


Mass: 489.922 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18ClF2N3O3S / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 2.35 Å3/Da / Density % sol: 47.71 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 100MM BISTRIS AT PH 6.0, 12.5% 2,5-HEXANEDIOL, AND 12% PEG3350, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Mar 28, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
Reflection twinOperator: -h,l,k / Fraction: 0.086
ReflectionResolution: 2.45→110.128 Å / Num. obs: 22230 / % possible obs: 99.8 % / Redundancy: 4.5 % / Rsym value: 0.072 / Net I/σ(I): 11.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.45-2.584.50.5241.41451531930.52499.9
2.58-2.744.60.3562.11393430060.35699.9
2.74-2.934.70.2323.31329128540.232100
2.93-3.164.60.15251239226790.152100
3.16-3.464.60.09281137224590.092100
3.46-3.874.60.06111.61013522270.06199.8
3.87-4.474.50.0513.3892219870.0599.8
4.47-5.484.30.04713.8738217010.04799.7
5.48-7.754.10.03519.3547513370.03599.4
7.75-104.4244.30.02420.133567870.02498.2

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Processing

Software
NameVersionClassificationNB
MOSFLM3.3.15data reduction
SCALA3.3.15data scaling
PHENIX1.5_2refinement
PDB_EXTRACT3.1data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.45→21.3 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7343 / Phase error: 32.22 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflectionSelection details
Rfree0.2575 1146 5.19 %RANDOM
Rwork0.2125 ---
all0.2143 22101 --
obs0.2143 21223 99.56 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 47.403 Å2 / ksol: 0.326 e/Å3
Displacement parametersBiso max: 205.71 Å2 / Biso mean: 65.2303 Å2 / Biso min: 12.44 Å2
Baniso -1Baniso -2Baniso -3
1-24.0938 Å2-0 Å2-0 Å2
2---6.2523 Å2-0 Å2
3----17.8415 Å2
Refinement stepCycle: LAST / Resolution: 2.45→21.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4002 0 33 65 4100
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034119
X-RAY DIFFRACTIONf_angle_d0.6495553
X-RAY DIFFRACTIONf_chiral_restr0.048600
X-RAY DIFFRACTIONf_plane_restr0.004707
X-RAY DIFFRACTIONf_dihedral_angle_d16.6341535
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4507-2.5620.31731420.33232570271294
2.562-2.69680.34151290.30232602273195
2.6968-2.86540.34661370.28372581271895
2.8654-3.08610.34981420.2692581272395
3.0861-3.39550.29771420.23192615275795
3.3955-3.88420.24051300.20122639276995
3.8842-4.88390.22281290.16792646277595
4.8839-21.27560.20141560.17662744290094
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)
10.42710.20920.19090.58130.53450.39050.02950.12940.05170.4450.08150.03080.28170.0987-0.08960.2830.02790.00650.1799-0.01490.1414-1.3512-12.829-19.0118
20.9070.0673-0.0545-0.02940.11361.4032-0.065-0.09990.53130.1643-0.0917-0.04310.62960.1890.1035-0.07930.0770.12640.1906-0.0440.03691.49178.62126.049
30.33240.08810.02560.22010.05360.0130.0039-0.01080.0148-0.0181-0.03940.02960.01730.00670.04850.22320.0830.06760.28430.05680.24481.8508-2.7808-20.087
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain AA449 - 720
2X-RAY DIFFRACTION2chain BB449 - 720
3X-RAY DIFFRACTION3chain L and resseq 1:1A1

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