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- PDB-8qqg: Structure of BRAF in Complex With Exarafenib (KIN-2787). -

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Basic information

Entry
Database: PDB / ID: 8qqg
TitleStructure of BRAF in Complex With Exarafenib (KIN-2787).
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE / Braf
Function / homology
Function and homology information


positive regulation of axon regeneration / 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 / ARMS-mediated activation / endothelial cell apoptotic process / myeloid progenitor cell differentiation / SHOC2 M1731 mutant abolishes MRAS complex function ...positive regulation of axon regeneration / 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 / 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 / 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 / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / centriolar satellite / cellular response to xenobiotic stimulus / epidermal growth factor receptor signaling pathway / long-term synaptic potentiation / 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 / T cell differentiation in thymus / T cell receptor signaling pathway / MAPK cascade / presynapse / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / postsynapse / neuron projection / 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 / 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-WJ9 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.979 Å
AuthorsSchmitt, A. / Costanzi, E. / Kania, R. / Chen, Y.K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Structure of BRAF in Complex With Exarafenib (KIN-2787).
Authors: Schmitt, A. / Costanzi, E. / Kania, R. / Chen, Y.K.
History
DepositionOct 4, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 24, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_entity_nonpoly / pdbx_entry_details
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_entry_details.has_protein_modification

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,86713
Polymers94,0543
Non-polymers1,81310
Water1,44180
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9795
Polymers31,3511
Non-polymers6284
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9444
Polymers31,3511
Non-polymers5923
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9444
Polymers31,3511
Non-polymers5923
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)206.778, 206.778, 149.382
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number98
Space group name H-MI4122
Components on special symmetry positions
IDModelComponents
11B-932-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
32A
42C
53B
63C

NCS domain segments:

Beg auth comp-ID: ASP / Beg label comp-ID: ASP / End auth comp-ID: LEU / End label comp-ID: LEU

Dom-IDComponent-IDEns-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111AA448 - 7202 - 274
221BB448 - 7202 - 274
332AA448 - 7202 - 274
442CC448 - 7202 - 274
553BB447 - 7201 - 274
663CC447 - 7201 - 274

NCS ensembles :
IDDetails
1Local NCS retraints between domains: 1 2
2Local NCS retraints between domains: 3 4
3Local NCS retraints between domains: 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: 31351.328 Da / Num. of mol.: 3
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-WJ9 / Exarafenib / (3~{S})-~{N}-[4-methyl-3-[2-morpholin-4-yl-6-[[(2~{R})-1-oxidanylpropan-2-yl]amino]pyridin-4-yl]phenyl]-3-[2,2,2-tris(fluoranyl)ethyl]pyrrolidine-1-carboxamide


Mass: 521.575 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H34F3N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 4.39 Å3/Da / Density % sol: 71.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 0.1 M Hepes pH 6.7, 3.9 M NaCl, 0.10 M SCN

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.999 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jul 13, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 2.979→146.214 Å / Num. obs: 29475 / % possible obs: 93.9 % / Redundancy: 15.9 % / CC1/2: 0.965 / Net I/σ(I): 6.9
Reflection shellResolution: 2.979→3.134 Å / Num. unique obs: 1472 / CC1/2: 0.359

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
pointlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.979→146.214 Å / Cor.coef. Fo:Fc: 0.906 / Cor.coef. Fo:Fc free: 0.859 / SU B: 19.721 / SU ML: 0.336 / Cross valid method: FREE R-VALUE / ESU R: 1.005 / ESU R Free: 0.385
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2612 522 1.771 %
Rwork0.2239 28954 -
all0.225 --
obs-28954 88.586 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 56.222 Å2
Baniso -1Baniso -2Baniso -3
1--0.089 Å20 Å2-0 Å2
2---0.089 Å20 Å2
3---0.178 Å2
Refinement stepCycle: LAST / Resolution: 2.979→146.214 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6388 0 118 80 6586
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0136517
X-RAY DIFFRACTIONr_bond_other_d0.0020.0176281
X-RAY DIFFRACTIONr_angle_refined_deg1.3491.668821
X-RAY DIFFRACTIONr_angle_other_deg1.0831.59714381
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7365791
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.66821.563320
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.57115.1441149
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg29.04206
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.9051541
X-RAY DIFFRACTIONr_dihedral_angle_6_deg11.9052012
X-RAY DIFFRACTIONr_dihedral_angle_other_6_deg11.286203
X-RAY DIFFRACTIONr_chiral_restr0.050.2849
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.027255
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021516
X-RAY DIFFRACTIONr_nbd_refined0.1540.21012
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1480.25242
X-RAY DIFFRACTIONr_nbtor_refined0.1450.23071
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0710.22851
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1220.2101
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0060.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1740.217
X-RAY DIFFRACTIONr_nbd_other0.1570.294
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0060.21
X-RAY DIFFRACTIONr_mcbond_it2.6086.2093185
X-RAY DIFFRACTIONr_mcbond_other2.6066.2083184
X-RAY DIFFRACTIONr_mcangle_it4.6559.2933969
X-RAY DIFFRACTIONr_mcangle_other4.6559.2943970
X-RAY DIFFRACTIONr_scbond_it1.9346.1313332
X-RAY DIFFRACTIONr_scbond_other1.9346.1313330
X-RAY DIFFRACTIONr_scangle_it3.599.1484852
X-RAY DIFFRACTIONr_scangle_other3.599.1484853
X-RAY DIFFRACTIONr_lrange_it6.93267.76823
X-RAY DIFFRACTIONr_lrange_other6.93267.7026821
X-RAY DIFFRACTIONr_ncsr_local_group_10.0450.052832
X-RAY DIFFRACTIONr_ncsr_local_group_20.0520.052908
X-RAY DIFFRACTIONr_ncsr_local_group_30.0330.052873
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.044550.05
12BX-RAY DIFFRACTIONLocal ncs0.044550.05
23AX-RAY DIFFRACTIONLocal ncs0.051770.05
24CX-RAY DIFFRACTIONLocal ncs0.051770.05
35BX-RAY DIFFRACTIONLocal ncs0.033460.05
36CX-RAY DIFFRACTIONLocal ncs0.033460.05
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.979-3.0560.29940.3233100.32324090.8020.76513.03450.319
3.056-3.140.222200.29812600.29723760.7670.77853.87210.299
3.14-3.2310.363320.29718920.29823030.7370.78483.54320.296
3.231-3.3310.294450.28320500.28322410.7840.80693.48510.281
3.331-3.440.292350.27120800.27121560.8010.84798.09830.265
3.44-3.560.313400.25920410.2621020.8090.85799.00090.251
3.56-3.6950.289330.27519860.27520340.7970.84699.26250.263
3.695-3.8460.265450.25519060.25519520.8390.84199.94880.242
3.846-4.0160.373230.24718580.24818810.8330.8781000.229
4.016-4.2120.25310.20517670.20617980.9090.9271000.192
4.212-4.440.154250.18717010.18617260.9560.9481000.175
4.44-4.7090.303340.16815920.17116260.910.9561000.157
4.709-5.0340.162270.17115000.1715270.9490.9561000.158
5.034-5.4360.208310.18914110.1914420.9510.9471000.175
5.436-5.9550.195280.20712930.20713210.960.9411000.191
5.955-6.6560.325170.21411890.21612060.9130.9341000.195
6.656-7.6830.189200.21510550.21410750.9360.9381000.199
7.683-9.4030.302130.1759080.1779210.8820.9641000.178
9.403-13.2710.288110.1797210.187320.9590.9691000.188
13.271-146.2140.36480.3464340.3464460.8860.87299.10310.349

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