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- PDB-6p7g: The co-crystal structure of BRAF(V600E) with PHI1 -

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Basic information

Entry
Database: PDB / ID: 6p7g
TitleThe co-crystal structure of BRAF(V600E) with PHI1
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / inhibitor / cancer / melanoma / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


CD4-positive, alpha-beta T cell differentiation / trehalose metabolism in response to stress / 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 ...CD4-positive, alpha-beta T cell differentiation / trehalose metabolism in response to stress / 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 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 / positive regulation of stress fiber assembly / response to cAMP / cellular response to calcium ion / ERK1 and ERK2 cascade / substrate adhesion-dependent cell spreading / cellular response to nerve growth factor stimulus / thymus development / 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 / visual learning / 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 receptor signaling pathway / regulation of cell population proliferation / cell body / T cell differentiation in thymus / scaffold protein binding / negative regulation of neuron apoptotic process / Ras protein signal transduction / 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) / 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 / 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
Chem-E7M / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.65 Å
AuthorsAgianian, B. / Gavathiotis, E.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA178394 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA204314 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA013330 United States
Citation
#1: Journal: Cancer Cell / Year: 2016
Title: An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling.
Authors: Karoulia, Z. / Wu, Y. / Ahmed, T.A. / Xin, Q. / Bollard, J. / Krepler, C. / Wu, X. / Zhang, C. / Bollag, G. / Herlyn, M. / Fagin, J.A. / Lujambio, A. / Gavathiotis, E. / Poulikakos, P.I.
History
DepositionJun 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 23, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_keywords / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_keywords.pdbx_keywords / _struct_keywords.text / _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)137,4689
Polymers135,0114
Non-polymers2,4585
Water90150
1
A: Serine/threonine-protein kinase B-raf
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,8385
Polymers67,5052
Non-polymers1,3323
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)68,6314
Polymers67,5052
Non-polymers1,1252
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)95.780, 108.790, 126.380
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: ASP / Beg label comp-ID: ASP / Refine code: _

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUAA449 - 72023 - 294
21GLUGLUBB449 - 72023 - 294
12GLUGLUAA449 - 72023 - 294
22GLUGLUCC449 - 72023 - 294
13GLUGLUAA449 - 72023 - 294
23GLUGLUDD449 - 72023 - 294
14LEULEUBB449 - 72123 - 295
24LEULEUCC449 - 72123 - 295
15LEULEUBB449 - 72123 - 295
25LEULEUDD449 - 72123 - 295
16LEULEUCC449 - 72123 - 295
26LEULEUDD449 - 72123 - 295

NCS ensembles :
ID
1
2
3
4
5
6

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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: 33752.668 Da / Num. of mol.: 4 / Fragment: Kinase domain residues 446-723
Mutation: I543A, I544S, I551K, Q562R, L588N, V600E, K630S, F667E, Y673S, A688R, L706S, Q709R, S713E, L716E, S720E, P722S, K723G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Plasmid: modified pET28 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): BL21-Codon Plus(DE3)-RIPL
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-E7M / 3-[(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-[4-({[2-(morpholin-4-yl)ethyl]amino}methyl)-3-(trifluoromethyl)phenyl]benzamide


Mass: 562.585 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C30H29F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NHE / 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID / N-CYCLOHEXYLTAURINE / CHES


Mass: 207.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H17NO3S / Comment: pH buffer*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / 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: 2.64 Å3/Da / Density % sol: 53.38 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 9 / Details: 0.1 M CHES/NaOH, 1 M Sodium Citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.03324 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 6, 2017
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03324 Å / Relative weight: 1
ReflectionResolution: 2.65→82.45 Å / Num. obs: 36800 / % possible obs: 94.9 % / Redundancy: 2.9 % / Rsym value: 0.289 / Net I/σ(I): 3
Reflection shellResolution: 2.65→2.79 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.966 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 5373 / Rsym value: 0.966 / % possible all: 96.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation6.16 Å82.45 Å
Translation6.16 Å82.45 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
SCALA3.3.22data scaling
PHASER2.7.17phasing
PDB_EXTRACT3.24data extraction
MOSFLM7.2.1data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.65→82.45 Å / Cor.coef. Fo:Fc: 0.905 / Cor.coef. Fo:Fc free: 0.878 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 2.364 / ESU R Free: 0.38 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.279 1875 5.1 %RANDOM
Rwork0.248 ---
obs0.249 34889 94.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 52.16 Å2
Baniso -1Baniso -2Baniso -3
1--2.21 Å20 Å20 Å2
2--2.67 Å20 Å2
3----0.46 Å2
Refinement stepCycle: LAST / Resolution: 2.65→82.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8316 0 177 50 8543
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0198681
X-RAY DIFFRACTIONr_bond_other_d00.028145
X-RAY DIFFRACTIONr_angle_refined_deg1.5151.95111697
X-RAY DIFFRACTIONr_angle_other_deg3.7032.9818902
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.10251031
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.19523.615390
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.232151579
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.971565
X-RAY DIFFRACTIONr_chiral_restr0.0910.21247
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219444
X-RAY DIFFRACTIONr_gen_planes_other0.0060.021773
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
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A157100.1
12B157100.1
21A158460.09
22C158460.09
31A154220.1
32D154220.1
41B156800.09
42C156800.09
51B154780.11
52D154780.11
61C155080.1
62D155080.1
LS refinement shellResolution: 2.65→2.72 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.407 133 -
Rwork0.404 2550 -
obs--95.51 %

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