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- PDB-5fd2: B-Raf wild-type kinase domain in complex with a purinylpyridinyla... -

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Basic information

Entry
Database: PDB / ID: 5fd2
TitleB-Raf wild-type kinase domain in complex with a purinylpyridinylamino-based inhibitor
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTransferase/Transferase Inhibitor / phosphotransferase / inhibitor / melanoma / 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 / 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 ...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 / 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 D-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 / MAP kinase kinase activity / synaptic vesicle exocytosis / somatic stem cell population maintenance / 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 / thymus development / cellular response to nerve growth factor stimulus / 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 / epidermal growth factor receptor signaling pathway / visual learning / 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 / Signaling by BRAF and RAF1 fusions / MAPK cascade / cellular response to xenobiotic stimulus / positive regulation of peptidyl-serine phosphorylation / 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 / 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) ...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 / 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-5XJ / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.89 Å
AuthorsWhittington, D.A. / Epstein, L.F.
CitationJournal: Bioorg.Med.Chem. / Year: 2016
Title: Purinylpyridinylamino-based DFG-in/ alpha C-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling.
Authors: Liu, L. / Lee, M.R. / Kim, J.L. / Whittington, D.A. / Bregman, H. / Hua, Z. / Lewis, R.T. / Martin, M.W. / Nishimura, N. / Potashman, M. / Yang, K. / Yi, S. / Vaida, K.R. / Epstein, L.F. / ...Authors: Liu, L. / Lee, M.R. / Kim, J.L. / Whittington, D.A. / Bregman, H. / Hua, Z. / Lewis, R.T. / Martin, M.W. / Nishimura, N. / Potashman, M. / Yang, K. / Yi, S. / Vaida, K.R. / Epstein, L.F. / Babij, C. / Fernando, M. / Carnahan, J. / Norman, M.H.
History
DepositionDec 15, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _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)69,9454
Polymers69,0522
Non-polymers8932
Water57632
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.790, 80.088, 245.253
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A1
2114B1

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.148307, -0.877989, -0.455126), (-0.928681, -0.281838, 0.241078), (-0.339936, 0.386914, -0.857171)34.588009, 64.279099, -67.786774

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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: 34525.898 Da / Num. of mol.: 2 / Fragment: UNP residues 433-726
Source method: isolated from a genetically manipulated source
Details: kinase domain / Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): BTI-Tn-5B1-4
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-5XJ / 6-[2-[[3-(dimethylsulfamoylamino)-2,6-bis(fluoranyl)phenyl]amino]pyridin-3-yl]-7~{H}-purine


Mass: 446.434 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H16F2N8O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 2.62 Å3/Da / Density % sol: 53.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: PEG 8000, tacsimate, tris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jun 13, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.88→50 Å / Num. obs: 16728 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 6.3 % / Biso Wilson estimate: 79.3 Å2 / Rmerge(I) obs: 0.101 / Rpim(I) all: 0.044 / Rrim(I) all: 0.11 / Χ2: 0.94 / Net I/av σ(I): 17.045 / Net I/σ(I): 8.9 / Num. measured all: 105310
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.88-2.986.20.7272.616320.7550.3160.7940.807100
2.98-3.16.60.51316290.8550.2160.5570.807100
3.1-3.246.70.38816420.9110.1620.4210.871100
3.24-3.416.60.27216690.9560.1150.2950.9100
3.41-3.636.50.17916690.980.0760.1950.962100
3.63-3.916.30.1316490.9890.0560.1411.21599.9
3.91-4.360.09716610.9930.0430.1071.11599.9
4.3-4.926.10.07716970.9950.0340.0841.01599.9
4.92-6.26.10.07916880.9940.0350.0860.96399.8
6.2-505.80.05417920.9970.0250.060.75499.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
HKL-2000data scaling
EPMRphasing
PDB_EXTRACT3.15data extraction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.89→50 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.856 / WRfactor Rfree: 0.2766 / WRfactor Rwork: 0.2125 / FOM work R set: 0.8167 / SU B: 30.219 / SU ML: 0.294 / SU R Cruickshank DPI: 0.3712 / SU Rfree: 0.4241 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.424 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2778 952 5.8 %RANDOM
Rwork0.2128 ---
obs0.2165 15408 97.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 199.83 Å2 / Biso mean: 52.9 Å2 / Biso min: 9.42 Å2
Baniso -1Baniso -2Baniso -3
1--0.6 Å20 Å20 Å2
2---0.39 Å20 Å2
3---0.98 Å2
Refinement stepCycle: final / Resolution: 2.89→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3978 0 62 32 4072
Biso mean--51 27.59 -
Num. residues----498
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.024131
X-RAY DIFFRACTIONr_bond_other_d0.0010.022821
X-RAY DIFFRACTIONr_angle_refined_deg1.21.9745584
X-RAY DIFFRACTIONr_angle_other_deg0.8333.0016847
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8535492
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.65923.667180
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.96315737
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4761526
X-RAY DIFFRACTIONr_chiral_restr0.0680.2612
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214493
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02835
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 41 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
MEDIUM POSITIONAL0.160.5
MEDIUM THERMAL23.242
LS refinement shellResolution: 2.887→2.962 Å
RfactorNum. reflection% reflection
Rfree0.372 51 -
Rwork0.304 770 -
obs--71.58 %
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)
12.6886-3.17130.23384.9886-2.21393.99560.00770.0263-0.5198-0.12220.0020.32860.20160.0489-0.00970.0882-0.02230.00730.0879-0.04620.336712.677926.72592.6504
22.79492.32080.23634.05150.47014.9893-0.12560.2734-0.0468-0.3050.22150.21020.112-0.0197-0.09590.0972-0.0946-0.03030.16380.02820.14111.520928.4278-19.9378
312.4001-1.0825-2.10950.8982-1.29343.68841.87441.0171-0.6609-0.9626-0.64980.34511.22750.0669-1.22462.42210.0033-0.98661.43250.23491.08079.089446.0918-63.86
45.90522.00721.87883.9855-0.30113.82130.02790.04070.1066-0.60550.13820.3614-0.0615-0.2943-0.16610.582-0.1956-0.18090.46210.06220.243316.69949.4796-38.839
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A448 - 533
2X-RAY DIFFRACTION2A534 - 720
3X-RAY DIFFRACTION3B449 - 533
4X-RAY DIFFRACTION4B534 - 720

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