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- PDB-4h58: BRAF in complex with compound 3 -

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Basic information

Entry
Database: PDB / ID: 4h58
TitleBRAF in complex with compound 3
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / structure based drug discovery / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Signalling to p38 via RIT and RIN / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / MAP kinase kinase activity / positive regulation of peptidyl-serine phosphorylation ...Signalling to p38 via RIT and RIN / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / MAP kinase kinase activity / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / postsynaptic modulation of chemical synaptic transmission / animal organ morphogenesis / cellular response to calcium ion / RAF activation / Signaling by high-kinase activity BRAF mutants / Spry regulation of FGF signaling / MAP2K and MAPK activation / 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 / MAPK cascade / Negative regulation of MAPK pathway / Signaling by BRAF and RAF1 fusions / cell body / scaffold protein binding / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / protein phosphorylation / non-specific serine/threonine protein kinase / postsynapse / neuron projection / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of gene expression / calcium ion binding / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-10Z / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsVasbinder, M. / Aquila, B. / Augustin, M. / Chueng, T. / Cook, D. / Drew, L. / Fauber, B. / Glossop, S. / Godin, R. / Grondine, M. ...Vasbinder, M. / Aquila, B. / Augustin, M. / Chueng, T. / Cook, D. / Drew, L. / Fauber, B. / Glossop, S. / Godin, R. / Grondine, M. / Hennessy, E. / Johannes, J. / Lee, S. / Lyne, P. / Moertl, M. / Omer, C. / Palakurthi, S. / Pontz, T. / Read, J. / Sha, L. / Shen, M. / Steinbacher, S. / Wang, H. / Wu, A. / Ye, M. / Bagal, B.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery and Optimization of a Novel Series of Potent Mutant B-Raf(V600E) Selective Kinase Inhibitors.
Authors: Vasbinder, M.M. / Aquila, B. / Augustin, M. / Chen, H. / Cheung, T. / Cook, D. / Drew, L. / Fauber, B.P. / Glossop, S. / Grondine, M. / Hennessy, E. / Johannes, J. / Lee, S. / Lyne, P. / ...Authors: Vasbinder, M.M. / Aquila, B. / Augustin, M. / Chen, H. / Cheung, T. / Cook, D. / Drew, L. / Fauber, B.P. / Glossop, S. / Grondine, M. / Hennessy, E. / Johannes, J. / Lee, S. / Lyne, P. / Mortl, M. / Omer, C. / Palakurthi, S. / Pontz, T. / Read, J. / Sha, L. / Shen, M. / Steinbacher, S. / Wang, H. / Wu, A. / Ye, M.
History
DepositionSep 18, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 27, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Sep 20, 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 / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)94,4755
Polymers94,0543
Non-polymers4212
Water27015
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,7372
Polymers31,3511
Non-polymers3851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase B-raf


Theoretical massNumber of molelcules
Total (without water)31,3511
Polymers31,3511
Non-polymers00
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)31,3872
Polymers31,3511
Non-polymers351
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)204.740, 204.740, 152.950
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number98
Space group name H-MI4122
Components on special symmetry positions
IDModelComponents
11B-801-

HOH

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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 / Fragment: protein kinase domain (UNP residues 448-722)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-10Z / N-(4-{[(2-methoxyethyl)amino]methyl}phenyl)-6-(pyridin-4-yl)quinazolin-2-amine


Mass: 385.462 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23N5O
#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.: 15 / 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: 4.26 Å3/Da / Density % sol: 71.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: salt, pH 6.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9999 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Dec 3, 2007 / Details: dynamically bendable mirror
RadiationMonochromator: LN2 cooled fixed-exit Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 3.1→47.25 Å / Num. all: 28238 / Num. obs: 28238 / % possible obs: 95.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Rmerge(I) obs: 0.14
Reflection shellResolution: 3.1→3.17 Å / Redundancy: 3 % / Rmerge(I) obs: 0.795 / % possible all: 85.9

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1UWH

1uwh


Resolution: 3.1→47.25 Å / Cor.coef. Fo:Fc: 0.916 / Cor.coef. Fo:Fc free: 0.87 / SU B: 18.585 / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 1.983 / ESU R Free: 0.422 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27158 1412 5 %RANDOM
Rwork0.22166 ---
all0.22413 26825 --
obs0.22413 26825 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 68.488 Å2
Baniso -1Baniso -2Baniso -3
1--1.52 Å20 Å20 Å2
2---1.52 Å20 Å2
3---3.04 Å2
Refinement stepCycle: LAST / Resolution: 3.1→47.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6367 0 30 15 6412
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0226639
X-RAY DIFFRACTIONr_bond_other_d0.0010.026124
X-RAY DIFFRACTIONr_angle_refined_deg1.2661.9778965
X-RAY DIFFRACTIONr_angle_other_deg0.789314264
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0125795
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.69523.811286
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.487151199
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6881540
X-RAY DIFFRACTIONr_chiral_restr0.0670.2980
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.027210
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021336
X-RAY DIFFRACTIONr_nbd_refined0.2190.21593
X-RAY DIFFRACTIONr_nbd_other0.1870.26485
X-RAY DIFFRACTIONr_nbtor_refined0.1840.23253
X-RAY DIFFRACTIONr_nbtor_other0.0870.23724
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.2158
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2180.221
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2050.298
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1020.22
X-RAY DIFFRACTIONr_mcbond_it1.1625188
X-RAY DIFFRACTIONr_mcbond_other0.10121623
X-RAY DIFFRACTIONr_mcangle_it1.32636430
X-RAY DIFFRACTIONr_scbond_it1.29743196
X-RAY DIFFRACTIONr_scangle_it2.01662535
LS refinement shellResolution: 3.1→3.182 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 96 -
Rwork0.359 1816 -
obs--100 %

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