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- PDB-4rzv: Crystal structure of the BRAF (R509H) kinase domain monomer bound... -

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Basic information

Entry
Database: PDB / ID: 4rzv
TitleCrystal structure of the BRAF (R509H) kinase domain monomer bound to Vemurafenib
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTransferase/Transferase Inhibitor / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


positive regulation of axon regeneration / 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 / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / myeloid progenitor cell differentiation / SHOC2 M1731 mutant abolishes MRAS complex function ...positive regulation of axon regeneration / 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 / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / myeloid progenitor cell differentiation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of D-glucose transmembrane transport / negative regulation of fibroblast migration / establishment of protein localization to membrane / positive regulation of axonogenesis / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / stress fiber assembly / face development / MAP kinase kinase activity / thyroid gland development / synaptic vesicle exocytosis / somatic stem cell population maintenance / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / postsynaptic modulation of chemical synaptic transmission / positive regulation of stress fiber assembly / ERK1 and ERK2 cascade / positive regulation of substrate adhesion-dependent cell spreading / substrate adhesion-dependent cell spreading / cellular response to calcium ion / thymus development / animal organ morphogenesis / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / centriolar satellite / cellular response to xenobiotic stimulus / epidermal growth factor receptor signaling pathway / long-term synaptic potentiation / 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 / Signaling by BRAF and RAF1 fusions / T cell differentiation in thymus / T cell receptor signaling pathway / MAPK cascade / presynapse / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / postsynapse / neuron projection / cilium / ciliary basal body / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / calcium ion binding / positive regulation of gene expression / negative regulation of apoptotic process / glutamatergic synapse / mitochondrion / zinc ion binding / ATP 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. / 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 / 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-032 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.994 Å
AuthorsWu, Y. / Gavathiotis, E.
CitationJournal: Cancer Cell / Year: 2016
Title: An integrated model of RAF inhibitor action predicts inhibitor activity against oncogenic BRAF signaling
Authors: Karoulia, Z. / Wu, Y. / Ahmed, T.A. / Qisheng, X. / Bollard, J. / Krepler, C. / Wu, X. / Zhang, C. / Bollag, G. / Herlym, M. / Fagin, J.A. / Lujambio, A. / Gavathiotis, E. / Poulikakos, P.I.
History
DepositionDec 24, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2017Group: Structure summary / Item: _chem_comp.pdbx_synonyms
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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

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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)65,0074
Polymers64,0272
Non-polymers9802
Water00
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5042
Polymers32,0141
Non-polymers4901
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)32,5042
Polymers32,0141
Non-polymers4901
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.975, 71.698, 243.281
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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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: 32013.674 Da / Num. of mol.: 2 / Fragment: Protein kinase domain residues 443-723
Mutation: R509H, I543A, I544S, I551K, Q562R, L588N, K630S, F667E, Y673S, A688R, L706S, Q709R, S713E, L716E, S720E, P722S, K723G
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: P15056, 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


Mass: 489.922 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H18ClF2N3O3S

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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: 2.21 Å3/Da / Density % sol: 44.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1 M Tris pH 7.0, 18% (w/v) PEG2000 MME , VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 17, 2013
RadiationMonochromator: mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.994→50 Å / Num. all: 11889 / Num. obs: 9880 / % possible obs: 83.1 % / Observed criterion σ(I): -3 / Rmerge(I) obs: 0.16
Reflection shellResolution: 2.994→3.09 Å / Rmerge(I) obs: 0.8 / % possible all: 86.3

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHASERphasing
PHENIX(phenix.refine: dev_1760)refinement
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3C4C

3c4c


Resolution: 2.994→44.767 Å / SU ML: 0.44 / σ(F): 1.34 / Phase error: 27.18 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2671 470 4.76 %
Rwork0.2042 --
obs0.2072 9871 82.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.994→44.767 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4252 0 66 0 4318
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034406
X-RAY DIFFRACTIONf_angle_d0.7145949
X-RAY DIFFRACTIONf_dihedral_angle_d13.7161647
X-RAY DIFFRACTIONf_chiral_restr0.025639
X-RAY DIFFRACTIONf_plane_restr0.003754
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.994-3.42760.33131520.2553180X-RAY DIFFRACTION85
3.4276-4.31790.28091720.20263114X-RAY DIFFRACTION84
4.3179-44.77190.23021460.18443107X-RAY DIFFRACTION80
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)
14.2312-0.66180.33588.2182-1.93985.4937-0.449-0.2777-0.40430.31470.2258-0.6297-0.0342-0.05550.16520.34610.0042-0.04870.4016-0.06090.320578.6308-1.238712.5651
22.55062.540.2664.68291.62044.37970.0661-0.04720.0842-0.2301-0.0517-0.3049-0.00240.0916-0.00750.18640.0350.00680.3399-0.04450.384880.833314.851418.4198
35.1070.63491.12944.952-2.62744.6385-0.19580.00770.86610.1674-0.134-0.5411-0.41690.63510.15310.3577-0.0714-0.02280.3956-0.13380.625991.495927.701222.8363
46.0034-1.13862.22924.6446-1.46883.1959-0.2677-1.09751.53350.24560.57310.6144-0.6423-0.3104-0.01870.3958-0.13730.01660.705-0.12560.748574.720529.459230.2957
56.5609-0.3899-0.34113.6096-1.07842.9408-0.09490.2109-0.39520.08520.35270.25450.0805-0.3689-0.28370.3245-0.0202-0.04220.4594-0.11410.399556.489117.120341.798
63.7059-0.52150.05245.220.96326.3861-0.2224-0.2591-0.02790.54790.1903-0.05860.05460.10120.04680.249-0.0028-0.0150.3971-0.01350.358775.373817.233452.3968
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 449 through 507 )
2X-RAY DIFFRACTION2chain 'A' and (resid 508 through 634 )
3X-RAY DIFFRACTION3chain 'A' and (resid 635 through 706 )
4X-RAY DIFFRACTION4chain 'A' and (resid 707 through 721 )
5X-RAY DIFFRACTION5chain 'B' and (resid 449 through 549 )
6X-RAY DIFFRACTION6chain 'B' and (resid 550 through 722 )

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