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- PDB-6b8u: Crystals Structure of B-Raf kinase domain in complex with an Imid... -

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Basic information

Entry
Database: PDB / ID: 6b8u
TitleCrystals Structure of B-Raf kinase domain in complex with an Imidazopyridinyl benzamide inhibitor
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTransferase/Transferase Inhibitor / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1 / ONCOPROTEIN / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


CD4-positive, alpha-beta T cell differentiation / positive regulation of axon regeneration / 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 / myeloid progenitor cell differentiation / endothelial cell apoptotic process / SHOC2 M1731 mutant abolishes MRAS complex function ...CD4-positive, alpha-beta T cell differentiation / positive regulation of axon regeneration / 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 / myeloid progenitor cell differentiation / endothelial cell apoptotic process / 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 / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / Negative regulation of MAPK pathway / centriolar satellite / long-term synaptic potentiation / cellular response to xenobiotic stimulus / epidermal growth factor receptor signaling 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 / MAPK cascade / presynapse / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / neuron projection / positive regulation of ERK1 and ERK2 cascade / protein phosphorylation / non-specific serine/threonine protein kinase / postsynapse / protein kinase activity / 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 / 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-8EN / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.68 Å
AuthorsAppleton, B.A. / Murray, J. / Shafer, C.M.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors.
Authors: Smith, A. / Ni, Z.J. / Poon, D. / Huang, Z. / Chen, Z. / Zhang, Q. / Tandeske, L. / Merritt, H. / Shoemaker, K. / Chan, J. / Kaufman, S. / Huh, K. / Murray, J. / Appleton, B.A. / Cowan- ...Authors: Smith, A. / Ni, Z.J. / Poon, D. / Huang, Z. / Chen, Z. / Zhang, Q. / Tandeske, L. / Merritt, H. / Shoemaker, K. / Chan, J. / Kaufman, S. / Huh, K. / Murray, J. / Appleton, B.A. / Cowan-Jacob, S.W. / Scheufler, C. / Kanazawa, T. / Jansen, J.M. / Stuart, D. / Shafer, C.M.
History
DepositionOct 9, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 22, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)64,7334
Polymers63,8282
Non-polymers9052
Water2,000111
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3662
Polymers31,9141
Non-polymers4521
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)32,3662
Polymers31,9141
Non-polymers4521
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)93.502, 93.502, 164.703
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: 31913.881 Da / Num. of mol.: 2 / Fragment: UNP residues 445-723
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Plasmid: pBlueBac4.5 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF21
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-8EN / ~{N}-[3-(2-acetamidoimidazo[1,2-a]pyridin-6-yl)-4-methyl-phenyl]-3-(trifluoromethyl)benzamide


Mass: 452.428 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H19F3N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 111 / 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: 2.82 Å3/Da / Density % sol: 56.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 4.7
Details: 10% PEG8000, 0.1 M sodium citrate pH 4.7, and 0.2 M sodium chloride

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: LN2
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11589 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 30, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11589 Å / Relative weight: 1
ReflectionResolution: 2.68→46.8 Å / Num. obs: 21143 / % possible obs: 100 % / Redundancy: 5.1 % / Biso Wilson estimate: 56.71 Å2 / Rmerge(I) obs: 0.152 / Rpim(I) all: 0.074 / Net I/σ(I): 11.4
Reflection shellResolution: 2.68→2.78 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.768 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 2056 / Rpim(I) all: 0.369 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
PROCESSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2FB8

2fb8


Resolution: 2.68→46.75 Å / Cor.coef. Fo:Fc: 0.9378 / Cor.coef. Fo:Fc free: 0.9196 / SU R Cruickshank DPI: 0.452 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.49 / SU Rfree Blow DPI: 0.259 / SU Rfree Cruickshank DPI: 0.258
RfactorNum. reflection% reflectionSelection details
Rfree0.2184 1085 5.15 %RANDOM
Rwork0.1784 ---
obs0.1804 21086 99.35 %-
Displacement parametersBiso mean: 41.24 Å2
Baniso -1Baniso -2Baniso -3
1--2.7573 Å20 Å20 Å2
2---2.7573 Å20 Å2
3---5.5147 Å2
Refine analyzeLuzzati coordinate error obs: 0.296 Å
Refinement stepCycle: 1 / Resolution: 2.68→46.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3944 0 66 111 4121
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014100HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.115546HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1419SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes85HARMONIC2
X-RAY DIFFRACTIONt_gen_planes652HARMONIC5
X-RAY DIFFRACTIONt_it4100HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.05
X-RAY DIFFRACTIONt_other_torsion18.68
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion528SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4643SEMIHARMONIC4
LS refinement shellResolution: 2.68→2.81 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2787 152 5.7 %
Rwork0.1991 2517 -
all0.2036 2669 -
obs--99.35 %
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)
11.639-0.54930.81390.7264-0.4641.31830.0679-0.0765-0.10170.0465-0.033-0.10370.07840.0727-0.0349-0.0715-0.0375-0.0036-0.03180.0467-0.091-20.85995.73371.272
21.0266-0.4530.52281.8802-1.19111.97080.07220.03410.22340.0793-0.03750.082-0.1967-0.0623-0.0347-0.11110.01620.0134-0.07630.0031-0.0672-41.485426.9649-14.4915
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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