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- PDB-5jrq: BRAFV600E Kinase Domain In Complex with Chemically Linked Vemuraf... -

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Basic information

Entry
Database: PDB / ID: 5jrq
TitleBRAFV600E Kinase Domain In Complex with Chemically Linked Vemurafenib Inhibitor VEM-6-VEM
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE inhibitor / kinase / dimer / 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 / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / 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 / presynapse / MAPK cascade / 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 / cytoplasm / 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) ...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-6N9 / TETRAMETHYLAMMONIUM ION / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.287 Å
AuthorsGrasso, M.J. / Marmorstein, R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA114046 United States
CitationJournal: Acs Chem.Biol. / Year: 2016
Title: Chemically Linked Vemurafenib Inhibitors Promote an Inactive BRAF(V600E) Conformation.
Authors: Grasso, M. / Estrada, M.A. / Ventocilla, C. / Samanta, M. / Maksimoska, J. / Villanueva, J. / Winkler, J.D. / Marmorstein, R.
History
DepositionMay 6, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 14, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 21, 2016Group: Database references
Revision 1.2Nov 2, 2016Group: Database references
Revision 1.3Sep 27, 2017Group: Author supporting evidence / Derived calculations / Category: pdbx_audit_support / pdbx_struct_oper_list
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 2.0Nov 2, 2022Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_2 / entity / pdbx_entity_nonpoly
Item: _atom_site.Cartn_x / _atom_site.Cartn_y ..._atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 2.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)65,1279
Polymers63,7592
Non-polymers1,3687
Water3,153175
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.836, 67.753, 67.881
Angle α, β, γ (deg.)90.000, 90.320, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Serine/threonine-protein kinase B-raf / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 31879.490 Da / Num. of mol.: 2 / Fragment: Kinase domain (UNP residues 448-723)
Mutation: I543A, I544S, I551K, Q562R, L588N, K630S, F667E, Y673S, A688R, L706S, Q709R, S713E, L716E, S720E, P722S, K723G, V600E
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

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Non-polymers , 5 types, 182 molecules

#2: Chemical ChemComp-6N9 / N-{2,4-difluoro-3-[5-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl}propane-1-sulfonamide


Mass: 485.503 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H21F2N3O4S
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-TMA / TETRAMETHYLAMMONIUM ION


Mass: 74.145 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H12N
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 175 / 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: 2.05 Å3/Da / Density % sol: 40.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 100mM Tris pH 8.5, 14% PEG Monomethyl Ether 2000, and 200mM Trimethyl Amine N-oxide Dihydrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.287→50 Å / Num. obs: 22366 / % possible obs: 96 % / Redundancy: 2.7 % / Biso Wilson estimate: 32.69 Å2 / Rmerge(I) obs: 0.097 / Χ2: 2.517 / Net I/av σ(I): 16.292 / Net I/σ(I): 10.8 / Num. measured all: 59386
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.287-2.342.70.52111701.79598.7
2.34-2.382.70.53711031.85197.6
2.38-2.432.70.47911381.96997.9
2.43-2.482.70.44211191.9997.6
2.48-2.532.70.37211512.13397.4
2.53-2.592.70.33311041.98797.4
2.59-2.662.70.32111182.12197.2
2.66-2.732.70.26211332.12996.8
2.73-2.812.70.23611172.24497.1
2.81-2.92.70.19211172.32997
2.9-32.70.15311332.50996.8
3-3.122.70.12211212.57996.5
3.12-3.262.70.11311132.84596.2
3.26-3.442.70.09311002.95695
3.44-3.652.70.07611093.23495.4
3.65-3.932.60.06810853.65893.4
3.93-4.332.50.05710973.61593.2
4.33-4.952.60.05210913.4392.9
4.95-6.242.60.04911292.86894.6
6.24-502.70.03811182.47292.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
PDB_EXTRACT3.2data extraction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WO5

4wo5


Resolution: 2.287→29.211 Å / FOM work R set: 0.7995 / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.17 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2538 1996 8.93 %
Rwork0.1947 20349 -
obs0.2001 22345 95.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 66.64 Å2 / Biso mean: 27.06 Å2 / Biso min: 10.77 Å2
Refinement stepCycle: final / Resolution: 2.287→29.211 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3828 0 174 175 4177
Biso mean--28.78 28.14 -
Num. residues----504
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083999
X-RAY DIFFRACTIONf_angle_d1.1785419
X-RAY DIFFRACTIONf_chiral_restr0.076599
X-RAY DIFFRACTIONf_plane_restr0.005681
X-RAY DIFFRACTIONf_dihedral_angle_d14.6531444
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2866-2.34370.32241280.24181307143587
2.3437-2.40710.30711420.22751490163298
2.4071-2.47790.32231460.22471469161597
2.4779-2.55780.32091290.22421473160298
2.5578-2.64920.28841490.21041492164197
2.6492-2.75520.26581480.21681484163297
2.7552-2.88050.29731460.21191457160397
2.8805-3.03220.29071470.20421465161297
3.0322-3.22190.27191440.19361478162296
3.2219-3.47030.23181410.18671444158595
3.4703-3.81890.221420.16931461160395
3.8189-4.36990.22291420.15791418156093
4.3699-5.49960.20381410.1791437157894
5.4996-29.21330.25251510.21371474162593

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