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- PDB-4cqe: B-Raf Kinase V600E mutant in complex with a diarylthiazole B-Raf ... -

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Basic information

Entry
Database: PDB / ID: 4cqe
TitleB-Raf Kinase V600E mutant in complex with a diarylthiazole B-Raf Inhibitor
ComponentsSLC45A3-BRAF FUSION PROTEIN
KeywordsTRANSFERASE / 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 / myeloid progenitor cell differentiation / endothelial cell apoptotic process / 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 / myeloid progenitor cell differentiation / endothelial cell apoptotic process / 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 / 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 / long-term synaptic potentiation / cellular response to xenobiotic stimulus / epidermal growth factor receptor signaling 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 / MAPK cascade / presynapse / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / neuron projection / positive regulation of ERK1 and ERK2 cascade / protein phosphorylation / non-specific serine/threonine protein kinase / postsynapse / protein kinase activity / ciliary basal body / cilium / 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-CQE / non-specific serine/threonine protein kinase / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsCasale, E. / Fasolini, M. / Pulici, M. / Traquandi, G. / Marchionni, C. / Modugno, M. / Lupi, R. / Amboldi, N. / Colombo, N. / Corti, L. ...Casale, E. / Fasolini, M. / Pulici, M. / Traquandi, G. / Marchionni, C. / Modugno, M. / Lupi, R. / Amboldi, N. / Colombo, N. / Corti, L. / Gasparri, F. / Pastori, W. / Scolaro, A. / Donati, D. / Felder, E. / Galvani, A. / Isacchi, A. / Pesenti, E. / Ciomei, M.
CitationJournal: Chemmedchem / Year: 2015
Title: Optimization of Diarylthiazole B-Raf Inhibitors: Identification of a Compound Endowed with High Oral Antitumor Activity, Mitigated Herg Inhibition, and Low Paradoxical Effect.
Authors: Pulici, M. / Traquandi, G. / Marchionni, C. / Modugno, M. / Lupi, R. / Amboldi, N. / Casale, E. / Colombo, N. / Corti, L. / Fasolini, M. / Gasparri, F. / Pastori, W. / Scolaro, A. / Donati, ...Authors: Pulici, M. / Traquandi, G. / Marchionni, C. / Modugno, M. / Lupi, R. / Amboldi, N. / Casale, E. / Colombo, N. / Corti, L. / Fasolini, M. / Gasparri, F. / Pastori, W. / Scolaro, A. / Donati, D. / Felder, E. / Galvani, A. / Isacchi, A. / Pesenti, E. / Ciomei, M.
History
DepositionFeb 14, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 10, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 11, 2015Group: Database references
Revision 1.2Feb 28, 2018Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.pdbx_collection_date
Revision 1.3Jan 30, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Experimental preparation / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / exptl_crystal_grow / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _exptl_crystal_grow.pdbx_details / _pdbx_database_status.status_code_sf / _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: SLC45A3-BRAF FUSION PROTEIN
B: SLC45A3-BRAF FUSION PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,4824
Polymers63,2262
Non-polymers1,2552
Water1,13563
1
A: SLC45A3-BRAF FUSION PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2412
Polymers31,6131
Non-polymers6281
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: SLC45A3-BRAF FUSION PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2412
Polymers31,6131
Non-polymers6281
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.605, 105.943, 109.889
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein SLC45A3-BRAF FUSION PROTEIN / SERINE THREONINE-PROTEIN KINASE B-RAF


Mass: 31613.238 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, RESIDUES 11-286 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: D7PBN4, UniProt: P15056*PLUS
#2: Chemical ChemComp-CQE / N-{4-[2-(1-cyclopropylpiperidin-4-yl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin-2-yl}acetamide


Mass: 627.700 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H28F3N5O3S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsRESIDUES G446 P447 ARE EXPRESSION TAG RESIDUES I543A I544S I551K Q562R L588N V600E K630S F667E ...RESIDUES G446 P447 ARE EXPRESSION TAG RESIDUES I543A I544S I551K Q562R L588N V600E K630S F667E Y673S A688R L706S Q709R S713E L716E S720E P722S K723G ARE ENGINEERED MUTATION

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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: 2.63 Å3/Da / Density % sol: 52.9 % / Description: NONE
Crystal growMethod: vapor diffusion, sitting drop
Details: 0.1M HEPES PH 7.5.0, 0.2 M MGCL2 AND 20% PEG6000, VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.98
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.3→40 Å / Num. obs: 28170 / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 6.1 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 15.2
Reflection shellResolution: 2.3→2.3 Å / Rmerge(I) obs: 0.35 / % possible all: 96.1

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3C4C

3c4c


Resolution: 2.3→30 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.928 / SU B: 6.984 / SU ML: 0.17 / Cross valid method: THROUGHOUT / ESU R: 0.314 / ESU R Free: 0.236 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.25519 1407 5 %RANDOM
Rwork0.20763 ---
obs0.21006 26565 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 51.359 Å2
Baniso -1Baniso -2Baniso -3
1-2.98 Å20 Å20 Å2
2---1.07 Å20 Å2
3----1.91 Å2
Refinement stepCycle: LAST / Resolution: 2.3→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3992 0 86 63 4141
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.024175
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.471.9835630
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6015491
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.63523.617188
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.32115763
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5761532
X-RAY DIFFRACTIONr_chiral_restr0.0940.2604
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213106
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 95 -
Rwork0.289 1716 -
obs--97.47 %

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