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- PDB-4g9r: B-Raf V600E Kinase Domain Bound to a Type II Dihydroquinazoline I... -

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Basic information

Entry
Database: PDB / ID: 4g9r
TitleB-Raf V600E Kinase Domain Bound to a Type II Dihydroquinazoline Inhibitor
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / Type II / Transferase / Kinase / 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-B1E / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsVoegtli, W.C. / Sturgis, H.L.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Pyrazolopyridine inhibitors of B-Raf(V600E). Part 4: Rational design and kinase selectivity profile of cell potent type II inhibitors.
Authors: Wenglowsky, S. / Moreno, D. / Laird, E.R. / Gloor, S.L. / Ren, L. / Risom, T. / Rudolph, J. / Sturgis, H.L. / Voegtli, W.C.
History
DepositionJul 24, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 14, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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

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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)71,3984
Polymers70,4952
Non-polymers9032
Water0
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6992
Polymers35,2481
Non-polymers4521
Water0
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)35,6992
Polymers35,2481
Non-polymers4521
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)96.820, 96.820, 168.718
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
DetailsProtein exists in equilibrium between monomer and dimer states

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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: Kinase Domain (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) / Strain (production host): High Five
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-B1E / 3-(2-cyanopropan-2-yl)-N-{4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}benzamide


Mass: 451.520 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H25N5O2

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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: 2.8 Å3/Da / Density % sol: 56.14 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 100 mM Tris, 16% PEG 8000, 100 mM NDSB-256, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 15, 2009
RadiationMonochromator: Synchrotron silicon crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.2→30 Å / Num. all: 13852 / Num. obs: 13727 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Rmerge(I) obs: 0.146 / Net I/σ(I): 5
Reflection shellResolution: 3.2→3.37 Å / Redundancy: 4 % / Rmerge(I) obs: 0.368 / Mean I/σ(I) obs: 2 / Num. unique all: 1957 / % possible all: 99.6

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Processing

Software
NameClassification
Blu-Icedata collection
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.2→29.24 Å / Cor.coef. Fo:Fc: 0.895 / Cor.coef. Fo:Fc free: 0.85 / SU B: 24.949 / SU ML: 0.415 / Cross valid method: THROUGHOUT / ESU R Free: 0.514 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2767 678 5 %RANDOM
Rwork0.22646 ---
obs0.22903 13001 100 %-
all-13852 --
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: 36.21 Å2
Baniso -1Baniso -2Baniso -3
1-0.82 Å20 Å20 Å2
2--0.82 Å20 Å2
3----1.64 Å2
Refinement stepCycle: LAST / Resolution: 3.2→29.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4174 0 68 0 4242
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0224336
X-RAY DIFFRACTIONr_angle_refined_deg1.0051.9785860
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1795519
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.47823.936188
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.45515785
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0661526
X-RAY DIFFRACTIONr_chiral_restr0.0720.2639
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.023248
X-RAY DIFFRACTIONr_nbd_refined0.1930.21999
X-RAY DIFFRACTIONr_nbtor_refined0.3060.22967
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1290.2119
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1860.241
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1030.22
X-RAY DIFFRACTIONr_mcbond_it0.3611.52663
X-RAY DIFFRACTIONr_mcangle_it0.65524198
X-RAY DIFFRACTIONr_scbond_it0.46931936
X-RAY DIFFRACTIONr_scangle_it0.834.51662
LS refinement shellResolution: 3.2→3.282 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.333 57 -
Rwork0.278 925 -
obs--100 %

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