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- PDB-5c9c: CRYSTAL STRUCTURE OF BRAF(V600E) IN COMPLEX WITH LY3009120 COMPND -

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Basic information

Entry
Database: PDB / ID: 5c9c
TitleCRYSTAL STRUCTURE OF BRAF(V600E) IN COMPLEX WITH LY3009120 COMPND
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...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 / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / negative regulation of fibroblast migration / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / positive regulation of axonogenesis / regulation of T cell differentiation / mitogen-activated protein kinase kinase binding / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / positive regulation of axon regeneration / stress fiber assembly / face development / MAP kinase kinase activity / synaptic vesicle exocytosis / thyroid gland development / somatic stem cell population maintenance / MAP kinase kinase kinase activity / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / response to cAMP / positive regulation of peptidyl-serine phosphorylation / positive regulation of stress fiber assembly / positive regulation of substrate adhesion-dependent cell spreading / ERK1 and ERK2 cascade / substrate adhesion-dependent cell spreading / cellular response to calcium ion / thymus development / animal organ morphogenesis / RAF activation / cellular response to nerve growth factor stimulus / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / response to peptide hormone / centriolar satellite / long-term synaptic potentiation / epidermal growth factor receptor signaling pathway / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / 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 / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / postsynapse / protein kinase activity / neuron projection / ciliary basal body / cilium / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / calcium ion binding / positive regulation of gene expression / protein-containing complex binding / negative regulation of apoptotic process / glutamatergic synapse / mitochondrion / zinc ion binding
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-4Z5 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsEdwards, T. / Abendroth, J. / Chun, L.
Citation
Journal: Cancer Cell / Year: 2015
Title: Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.
Authors: Peng, S.B. / Henry, J.R. / Kaufman, M.D. / Lu, W.P. / Smith, B.D. / Vogeti, S. / Rutkoski, T.J. / Wise, S. / Chun, L. / Zhang, Y. / Van Horn, R.D. / Yin, T. / Zhang, X. / Yadav, V. / Chen, S. ...Authors: Peng, S.B. / Henry, J.R. / Kaufman, M.D. / Lu, W.P. / Smith, B.D. / Vogeti, S. / Rutkoski, T.J. / Wise, S. / Chun, L. / Zhang, Y. / Van Horn, R.D. / Yin, T. / Zhang, X. / Yadav, V. / Chen, S.H. / Gong, X. / Ma, X. / Webster, Y. / Buchanan, S. / Mochalkin, I. / Huber, L. / Kays, L. / Donoho, G.P. / Walgren, J. / McCann, D. / Patel, P. / Conti, I. / Plowman, G.D. / Starling, J.J. / Flynn, D.L.
#1: Journal: J.Med.Chem. / Year: 2015
Title: Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical ...Title: Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells.
Authors: Henry, J.R. / Kaufman, M.D. / Peng, S.B. / Ahn, Y.M. / Caldwell, T.M. / Vogeti, L. / Telikepalli, H. / Lu, W.P. / Hood, M.M. / Rutkoski, T.J. / Smith, B.D. / Vogeti, S. / Miller, D. / Wise, ...Authors: Henry, J.R. / Kaufman, M.D. / Peng, S.B. / Ahn, Y.M. / Caldwell, T.M. / Vogeti, L. / Telikepalli, H. / Lu, W.P. / Hood, M.M. / Rutkoski, T.J. / Smith, B.D. / Vogeti, S. / Miller, D. / Wise, S.C. / Chun, L. / Zhang, X. / Zhang, Y. / Kays, L. / Hipskind, P.A. / Wrobleski, A.D. / Lobb, K.L. / Clay, J.M. / Cohen, J.D. / Walgren, J.L. / McCann, D. / Patel, P. / Clawson, D.K. / Guo, S. / Manglicmot, D. / Groshong, C. / Logan, C. / Starling, J.J. / Flynn, D.L.
History
DepositionJun 26, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2015Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)71,3805
Polymers70,4952
Non-polymers8843
Water2,432135
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6722
Polymers35,2481
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)35,7083
Polymers35,2481
Non-polymers4602
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2410 Å2
ΔGint-18 kcal/mol
Surface area22730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.880, 93.880, 165.550
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 35247.617 Da / Num. of mol.: 2 / Fragment: unp residues 432-726 / Mutation: V600E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-4Z5 / 1-(3,3-dimethylbutyl)-3-{2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl}urea / LY3009120


Mass: 424.514 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H29FN6O
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 135 / 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: 2.59 Å3/Da / Density % sol: 52.5 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: 26% PEG 3350, 50 MM AMMONIUM CITRATE, 50 MM SODIUM FLORIDE, 2 MG/ML PROTEIN, 5-FOLD MOLAR EXCESS DP4978; CRYSTAL ID 215552F10, SITTING DROP VAPOR DIFFUSION, TEMPERATURE 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 11, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 20853 / % possible obs: 99.1 % / Observed criterion σ(I): -3 / Redundancy: 6.2 % / Biso Wilson estimate: 33.92 Å2 / Rmerge(I) obs: 0.127 / Net I/σ(I): 12.25
Reflection shellResolution: 2.7→2.77 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.591 / Mean I/σ(I) obs: 2.9 / % possible all: 99.9

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.5.0109refinement
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1uwh

1uwh


Resolution: 2.7→50 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.902 / SU B: 9.913 / SU ML: 0.205 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.623 / ESU R Free: 0.301 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE
RfactorNum. reflection% reflectionSelection details
Rfree0.238 1044 5 %RANDOM
Rwork0.194 ---
obs0.196 20740 98.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.92 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20 Å20 Å2
2--0.57 Å20 Å2
3----1.13 Å2
Refinement stepCycle: LAST / Resolution: 2.7→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3944 0 63 135 4142
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0224108
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6051.9755570
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1075503
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.28624.024169
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.37215703
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.891520
X-RAY DIFFRACTIONr_chiral_restr0.1090.2621
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213051
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_it0.8331.52513
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.58824041
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.10331595
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.6174.51527
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: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 77 -
Rwork0.263 1433 -
obs--99.15 %

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