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

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Basic information

Entry
Database: PDB / ID: 5jsm
TitleBRAFV600E Kinase Domain In Complex with Chemically Linked Vemurafenib Inhibitor VEM-3-VEM
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE inhibitor / kinase / dimer / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


CD4-positive, alpha-beta T cell differentiation / positive regulation of axon regeneration / 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 ...CD4-positive, alpha-beta T cell differentiation / positive regulation of axon regeneration / 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 / positive regulation of peptidyl-serine phosphorylation / somatic stem cell population maintenance / 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 / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / Negative regulation of MAPK pathway / centriolar satellite / cellular response to xenobiotic stimulus / epidermal growth factor receptor signaling pathway / long-term synaptic potentiation / 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 / presynapse / T cell receptor signaling pathway / MAPK cascade / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / neuron projection / protein phosphorylation / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / protein kinase activity / postsynapse / 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-6NB / BENZAMIDINE / ETHANOL / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.19 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 8, 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: Advisory / Author supporting evidence / Derived calculations
Category: pdbx_audit_support / pdbx_database_PDB_obs_spr / 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 1.5Apr 13, 2022Group: Database references / Category: database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.6Apr 27, 2022Group: Advisory / Category: pdbx_database_PDB_obs_spr
Revision 1.7Sep 27, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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
C: Serine/threonine-protein kinase B-raf
D: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)130,67821
Polymers127,5184
Non-polymers3,16017
Water5,242291
1
A: Serine/threonine-protein kinase B-raf
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,67015
Polymers63,7592
Non-polymers1,91113
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Serine/threonine-protein kinase B-raf
D: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0086
Polymers63,7592
Non-polymers1,2494
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)64.608, 68.258, 276.007
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain B
21chain C

NCS domain segments:

Component-ID: 1 / Ens-ID: 1

Dom-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1GLYGLYLEULEUchain BBB444 - 7211 - 278
2SERSERSERSERchain CCC445 - 7222 - 279

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Components

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Protein , 1 types, 4 molecules ABCD

#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.: 4 / 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 , 7 types, 308 molecules

#2: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-BEN / BENZAMIDINE


Mass: 120.152 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H8N2
#4: Chemical ChemComp-EOH / ETHANOL


Mass: 46.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O
#5: Chemical ChemComp-6NB / N,N'-{ethane-1,2-diylbis[oxyethane-2,1-diyloxy-4,1-phenylene-1H-pyrrolo[2,3-b]pyridine-5,3-diylcarbonyl(2,4-difluoro-3,1-phenylene)]}di(propane-1-sulfonamide)


Mass: 1057.095 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C52H48F4N6O10S2
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 291 / 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: 2.39 Å3/Da / Density % sol: 48.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 100mM Tris pH 8.5, 5% Ethanol, 2% Benzamidine HCl

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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: Feb 28, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.19→138 Å / Num. obs: 63449 / % possible obs: 99.3 % / Redundancy: 12.9 % / Biso Wilson estimate: 51.44 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.104 / Rpim(I) all: 0.03 / Rrim(I) all: 0.109 / Net I/σ(I): 15.6 / Num. measured all: 820448
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.19-2.2412.12.3235208642950.5920.6862.4261.397.5
10.04-13811.10.04888617960.9990.0150.05148.299.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
Aimless0.1.27data scaling
PHASERphasing
PDB_EXTRACT3.2data extraction
Cootmodel building
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JRQ

5jrq


Resolution: 2.19→62.908 Å / FOM work R set: 0.756 / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2597 2000 3.16 %
Rwork0.2072 61235 -
obs0.2089 63235 98.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 106.72 Å2 / Biso mean: 50.06 Å2 / Biso min: 20.64 Å2
Refinement stepCycle: final / Resolution: 2.19→62.908 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8238 0 286 291 8815
Biso mean--47.41 45.66 -
Num. residues----1049
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0098671
X-RAY DIFFRACTIONf_angle_d1.19511703
X-RAY DIFFRACTIONf_chiral_restr0.0471262
X-RAY DIFFRACTIONf_plane_restr0.0051480
X-RAY DIFFRACTIONf_dihedral_angle_d16.8243290
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11B2329X-RAY DIFFRACTION11.197TORSIONAL
12C2329X-RAY DIFFRACTION11.197TORSIONAL
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 (%)
2.19-2.24480.36751470.32444126427395
2.2448-2.30550.34511400.30094290443098
2.3055-2.37330.33371300.27714275440599
2.3733-2.44990.29891480.26664323447199
2.4499-2.53750.31971330.2514361449499
2.5375-2.63910.29821440.24684319446399
2.6391-2.75920.34361300.24294409453999
2.7592-2.90470.32311530.243643294482100
2.9047-3.08660.26231400.217844174557100
3.0866-3.3250.27481450.21144293443898
3.325-3.65950.26721390.198944554594100
3.6595-4.1890.24421530.182644464599100
4.189-5.27730.18991480.170445234671100
5.2773-62.93340.25161500.20194669481998

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