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- PDB-8c7x: Crystal structure of BRAF in complex with a hybrid compound 6 -

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Basic information

Entry
Database: PDB / ID: 8c7x
TitleCrystal structure of BRAF in complex with a hybrid compound 6
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE / BRAF / kinase / kinase inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


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 / 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 ...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 / 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 D-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 / MAP kinase kinase activity / synaptic vesicle exocytosis / somatic stem cell population maintenance / thyroid gland development / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of stress fiber assembly / response to cAMP / ERK1 and ERK2 cascade / cellular response to calcium ion / substrate adhesion-dependent cell spreading / thymus development / cellular response to nerve growth factor stimulus / long-term synaptic potentiation / animal organ morphogenesis / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / epidermal growth factor receptor signaling pathway / visual learning / 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 / Signaling by BRAF and RAF1 fusions / MAPK cascade / cellular response to xenobiotic stimulus / positive regulation of peptidyl-serine phosphorylation / presynapse / T cell receptor signaling pathway / regulation of cell population proliferation / T cell differentiation in thymus / cell body / 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 / intracellular membrane-bounded organelle / protein serine kinase activity / 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) ...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 / 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
Similarity search - Domain/homology
BROMIDE ION / Chem-TXV / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsChaikuad, A. / Bonnet, P. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor.
Authors: Arora, R. / Linders, J.T.M. / Aci-Seche, S. / Verheyen, T. / Van Heerde, E. / Brehmer, D. / Chaikuad, A. / Knapp, S. / Bonnet, P.
History
DepositionJan 17, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 19, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)66,75324
Polymers64,5002
Non-polymers2,25322
Water8,989499
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5970 Å2
ΔGint44 kcal/mol
Surface area24680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.129, 97.560, 114.900
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 Serine/threonine-protein kinase B-raf / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 32249.941 Da / Num. of mol.: 2
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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Br
#4: Chemical ChemComp-TXV / ~{N}-[3-[(5-chloranyl-1~{H}-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-bis(fluoranyl)phenyl]-3-(2-cyanopropan-2-yl)benzamide


Mass: 478.878 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H17ClF2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 499 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.13 Å3/Da / Density % sol: 42.38 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 19% PEG3350, 0.1M bis-tris-propane pH 7.0, 0.2M sodium bromide, 10% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97624 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97624 Å / Relative weight: 1
ReflectionResolution: 1.65→57.45 Å / Num. obs: 66629 / % possible obs: 99.1 % / Redundancy: 8.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.024 / Rrim(I) all: 0.07 / Net I/σ(I): 21.2
Reflection shellResolution: 1.65→1.74 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.166 / Mean I/σ(I) obs: 9.4 / Num. unique obs: 9169 / CC1/2: 0.982 / Rpim(I) all: 0.066 / Rrim(I) all: 0.179

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Processing

Software
NameVersionClassification
REFMAC5.8.0124refinement
SCALAdata scaling
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→74.37 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.957 / SU B: 2.398 / SU ML: 0.045 / Cross valid method: THROUGHOUT / ESU R: 0.088 / ESU R Free: 0.081 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17119 3282 4.9 %RANDOM
Rwork0.15346 ---
obs0.15434 63277 98.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 18.03 Å2
Baniso -1Baniso -2Baniso -3
1--0.85 Å2-0 Å2-0 Å2
2---0.69 Å20 Å2
3---1.54 Å2
Refinement stepCycle: 1 / Resolution: 1.65→74.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4273 0 139 499 4911
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0194575
X-RAY DIFFRACTIONr_bond_other_d0.0090.024463
X-RAY DIFFRACTIONr_angle_refined_deg1.5691.9536160
X-RAY DIFFRACTIONr_angle_other_deg1.461310261
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9035561
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.71123.725204
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.88415834
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9371534
X-RAY DIFFRACTIONr_chiral_restr0.0990.2662
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.025356
X-RAY DIFFRACTIONr_gen_planes_other0.0080.021062
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_it1.1081.0762169
X-RAY DIFFRACTIONr_mcbond_other1.1081.0742168
X-RAY DIFFRACTIONr_mcangle_it1.9311.6032713
X-RAY DIFFRACTIONr_mcangle_other1.9311.6062714
X-RAY DIFFRACTIONr_scbond_it1.4281.2572406
X-RAY DIFFRACTIONr_scbond_other1.4281.2572407
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.3291.8033434
X-RAY DIFFRACTIONr_long_range_B_refined6.0079.6855610
X-RAY DIFFRACTIONr_long_range_B_other6.0089.6855608
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 30000 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.15 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.65→1.693 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.19 227 -
Rwork0.157 4213 -
obs--90.5 %
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)
10.3876-0.00320.02230.1881-0.11890.2613-0.0043-0.01240.00940.0302-0.0119-0.0366-0.02160.00920.01610.05730.0035-0.00390.0454-0.00140.01225.553109.29716.309
22.02821.16790.47213.05051.57811.28330.0956-0.110.0735-0.0789-0.058-0.0556-0.1347-0.0844-0.03770.08840.01480.01080.0623-0.00610.006822.745119.42316.321
30.24530.0360.07360.5385-0.12090.1923-0.03310.0082-0.01820.01530.0291-0.0168-0.0155-0.02890.0040.05230.0087-0.00050.0584-0.00110.00376.962121.0258.08
40.5876-0.2078-0.0690.76440.27590.3580.00760.0014-0.04560.0485-0.02010.09680.0378-0.02590.01250.0606-0.00110.0120.03730.01050.019516.63288.39719.043
50.73730.0886-0.03840.79630.03920.6872-0.03030.0401-0.0495-0.03350.0117-0.02530.07770.01440.01860.06140.01290.01030.0386-0.00340.00532.79376.64313.161
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A449 - 585
2X-RAY DIFFRACTION2A586 - 613
3X-RAY DIFFRACTION3A614 - 722
4X-RAY DIFFRACTION4B448 - 569
5X-RAY DIFFRACTION5B570 - 722

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