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- PDB-5jt2: BRAFV600E Kinase Domain In Complex with Chemically Linked Vemuraf... -

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Basic information

Entry
Database: PDB / ID: 5jt2
TitleBRAFV600E Kinase Domain In Complex with Chemically Linked Vemurafenib Inhibitor VEM-BISAMIDE
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE inhibitor / kinase / dimer / 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 / 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 / MAP kinase kinase activity / thyroid gland development / 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 / 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 / mitochondrion / ATP binding / identical protein binding / nucleus / plasma membrane / 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 / 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-6NC / BENZAMIDINE / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.702 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 9, 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.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _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

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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)129,8928
Polymers127,5184
Non-polymers2,3744
Water3,135174
1
A: Serine/threonine-protein kinase B-raf
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0665
Polymers63,7592
Non-polymers1,3073
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)64,8263
Polymers63,7592
Non-polymers1,0671
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.102, 68.442, 275.603
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 A and segid
21chain B and segid
31chain C and segid
41chain D and segid

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111chain A and segidA0
211chain B and segidB0
311chain C and segidC0
411chain D and segidD0

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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: 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
#2: Chemical ChemComp-BEN / BENZAMIDINE / Benzamidine


Mass: 120.152 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H8N2
#3: Chemical ChemComp-6NC / 2,2'-oxybis(N-{[4-(3-{2,6-difluoro-3-[(propane-1-sulfonyl)amino]benzoyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]methyl}acetamide)


Mass: 1067.093 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C52H46F4N8O9S2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 174 / 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: 2.41 Å3/Da / Density % sol: 48.91 %
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: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Oct 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 34678 / % possible obs: 99.6 % / Redundancy: 5.5 % / Biso Wilson estimate: 57.39 Å2 / Rmerge(I) obs: 0.099 / Rpim(I) all: 0.046 / Rrim(I) all: 0.11 / Χ2: 1.375 / Net I/av σ(I): 22.174 / Net I/σ(I): 8.2 / Num. measured all: 192419
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.7-2.755.80.5416900.8620.240.5920.50799.9
2.75-2.85.90.46316940.8940.2030.5070.507100
2.8-2.855.90.41317320.9250.1810.4520.563100
2.85-2.915.90.33516720.9360.1470.3670.558100
2.91-2.975.80.26917420.9540.1190.2950.646100
2.97-3.045.90.25116990.9620.110.2750.684100
3.04-3.125.70.20617240.9720.0920.2260.755100
3.12-3.25.80.17516930.9750.0780.1920.866100
3.2-3.35.70.15617280.9850.0710.1721.01999.9
3.3-3.45.70.15117300.9850.0680.1661.138100
3.4-3.525.60.14517160.9860.0660.161.26799.8
3.52-3.665.40.12117170.990.0560.1341.46499.2
3.66-3.835.50.10417520.9910.0470.1141.67799.9
3.83-4.035.50.10217190.990.0470.1132.01399.7
4.03-4.295.40.08517570.9920.0390.0942.38799.9
4.29-4.625.30.07817300.9920.0360.0862.41799.9
4.62-5.085.20.07417510.9940.0350.0822.4899.7
5.08-5.815.10.07317880.9940.0360.0822.0799.6
5.81-7.3250.06717970.9960.0330.0752.05499.4
7.32-504.80.05518470.9960.0280.0623.18695.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
SCALEPACKdata scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
Cootmodel building
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JSM

5jsm


Resolution: 2.702→29.585 Å / FOM work R set: 0.7835 / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.99 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2729 1999 5.77 %
Rwork0.2122 32619 -
obs0.2158 34618 99.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 96.75 Å2 / Biso mean: 41.07 Å2 / Biso min: 11 Å2
Refinement stepCycle: final / Resolution: 2.702→29.585 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7605 0 272 174 8051
Biso mean--32.9 36.11 -
Num. residues----993
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0097942
X-RAY DIFFRACTIONf_angle_d1.27810753
X-RAY DIFFRACTIONf_chiral_restr0.0531179
X-RAY DIFFRACTIONf_plane_restr0.0071359
X-RAY DIFFRACTIONf_dihedral_angle_d14.0472822
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A4481X-RAY DIFFRACTION11.452TORSIONAL
12B4481X-RAY DIFFRACTION11.452TORSIONAL
13C4481X-RAY DIFFRACTION11.452TORSIONAL
14D4481X-RAY DIFFRACTION11.452TORSIONAL
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 (%)
2.7017-2.76920.30811410.24132248238999
2.7692-2.84410.34791380.25223172455100
2.8441-2.92770.34921420.249322752417100
2.9277-3.02210.32861300.225423182448100
3.0221-3.130.30591620.216323092471100
3.13-3.25520.27271350.215823282463100
3.2552-3.40310.31891380.224322872425100
3.4031-3.58220.28051380.23372306244499
3.5822-3.80620.27371430.209123362479100
3.8062-4.09940.25511440.203623262470100
4.0994-4.51070.23811500.176323292479100
4.5107-5.16040.2381410.18223502491100
5.1604-6.49020.28851450.218624132558100
6.4902-29.58650.25431520.22822477262998

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