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- PDB-6n0q: BRAF in complex with N-(4-methyl-3-(1-methyl-2-oxo-2,3-dihydro-1H... -

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Basic information

Entry
Database: PDB / ID: 6n0q
TitleBRAF in complex with N-(4-methyl-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)-3-(trifluoromethyl)benzamide.
ComponentsSerine/threonine-protein kinase B-raf
Keywordstransferase/transferase inhibitor / Raf / bRaf / cRaf / CRAF kinase / TRANSFERASE / 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 / positive regulation of stress fiber assembly / response to cAMP / 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 / cell body / positive regulation of peptidyl-serine phosphorylation / T cell differentiation in thymus / 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 / neuron projection / protein kinase activity / 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-K7S / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.04 Å
AuthorsMamo, M. / Appleton, B.A.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Design and Discovery ofN-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor ...Title: Design and Discovery ofN-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic.
Authors: Ramurthy, S. / Taft, B.R. / Aversa, R.J. / Barsanti, P.A. / Burger, M.T. / Lou, Y. / Nishiguchi, G.A. / Rico, A. / Setti, L. / Smith, A. / Subramanian, S. / Tamez, V. / Tanner, H. / Wan, L. ...Authors: Ramurthy, S. / Taft, B.R. / Aversa, R.J. / Barsanti, P.A. / Burger, M.T. / Lou, Y. / Nishiguchi, G.A. / Rico, A. / Setti, L. / Smith, A. / Subramanian, S. / Tamez, V. / Tanner, H. / Wan, L. / Hu, C. / Appleton, B.A. / Mamo, M. / Tandeske, L. / Tellew, J.E. / Huang, S. / Yue, Q. / Chaudhary, A. / Tian, H. / Iyer, R. / Hassan, A.Q. / Mathews Griner, L.A. / La Bonte, L.R. / Cooke, V.G. / Van Abbema, A. / Merritt, H. / Gampa, K. / Feng, F. / Yuan, J. / Mishina, Y. / Wang, Y. / Haling, J.R. / Vaziri, S. / Hekmat-Nejad, M. / Polyakov, V. / Zang, R. / Sethuraman, V. / Amiri, P. / Singh, M. / Sellers, W.R. / Lees, E. / Shao, W. / Dillon, M.P. / Stuart, D.D.
History
DepositionNov 7, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6794
Polymers63,8282
Non-polymers8512
Water6,197344
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3392
Polymers31,9141
Non-polymers4251
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3392
Polymers31,9141
Non-polymers4251
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)94.320, 94.320, 162.340
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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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: 31913.881 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: unidentified baculovirus
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-K7S / N-[4-methyl-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)phenyl]-3-(trifluoromethyl)benzamide


Mass: 425.403 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H18F3N3O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 344 / 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: 3.09 Å3/Da / Density % sol: 60.17 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 100 mM Tris pH 8.3, 15% PEG8000, and 25% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 15, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.04→51.53 Å / Num. obs: 46389 / % possible obs: 97.4 % / Redundancy: 11.4 % / Biso Wilson estimate: 36.25 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.107 / Rpim(I) all: 0.033 / Rrim(I) all: 0.113 / Net I/σ(I): 16.7 / Num. measured all: 528042 / Scaling rejects: 64
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.04-2.1511.70.99668470.7640.3041.042100
6.45-51.5310.50.027171410.0090.02999.9

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Processing

Software
NameVersionClassification
Aimless0.7.1data scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.24data extraction
Adxvdata reduction
PHASERphasing
RefinementResolution: 2.04→51.53 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.938 / SU R Cruickshank DPI: 0.149 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.158 / SU Rfree Blow DPI: 0.14 / SU Rfree Cruickshank DPI: 0.137
RfactorNum. reflection% reflectionSelection details
Rfree0.213 2346 5.07 %RANDOM
Rwork0.181 ---
obs0.182 46306 97.4 %-
Displacement parametersBiso max: 139.95 Å2 / Biso mean: 42.23 Å2 / Biso min: 17.54 Å2
Baniso -1Baniso -2Baniso -3
1-0.062 Å20 Å20 Å2
2--0.062 Å20 Å2
3----0.1241 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 2.04→51.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4057 0 124 344 4525
Biso mean--38.59 50.95 -
Num. residues----511
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1487SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes828HARMONIC5
X-RAY DIFFRACTIONt_it4289HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion543SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies4HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5294SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4289HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5813HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion3.24
X-RAY DIFFRACTIONt_other_torsion15.89
LS refinement shellResolution: 2.04→2.05 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2234 49 5.29 %
Rwork0.2165 878 -
all0.2168 927 -
obs--97.73 %
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)
11.5327-0.76221.28150.6583-0.54841.7664-0.1449-0.08320.11410.05820.0702-0.25140.00720.03190.0748-0.0715-0.0046-0.0329-0.07940.0001-0.0398-19.72614.91013.3879
20.6542-0.51040.6051.4102-1.14711.2467-0.0665-0.00620.21170.02730.0125-0.0669-0.1493-0.04870.054-0.0569-0.0053-0.0185-0.04890.0189-0.0508-41.331725.8744-11.8277
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A446 - 721
2X-RAY DIFFRACTION2{ B|* }B448 - 721

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