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- PDB-4pp7: Highly Potent and Selective 3-N-methylquinazoline-4(3H)-one Based... -

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Basic information

Entry
Database: PDB / ID: 4pp7
TitleHighly Potent and Selective 3-N-methylquinazoline-4(3H)-one Based Inhibitors of B-RafV600E Kinase
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / serine/threonine-protein kinase B-Raf / 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-2VX / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.4 Å
AuthorsWenglowsky, S. / Ren, L. / Grina, J. / Hansen, J.D. / Laird, E.R. / Moreno, D. / Dinkel, V. / Gloor, S.L. / Hastings, G. / Rana, S. ...Wenglowsky, S. / Ren, L. / Grina, J. / Hansen, J.D. / Laird, E.R. / Moreno, D. / Dinkel, V. / Gloor, S.L. / Hastings, G. / Rana, S. / Rasor, K. / Sturgis, H.L. / Voegtli, W.C. / Vigers, G.P.A. / Willis, B. / Mathieu, S. / Rudolph, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-Raf(V600E) kinase.
Authors: Wenglowsky, S. / Ren, L. / Grina, J. / Hansen, J.D. / Laird, E.R. / Moreno, D. / Dinkel, V. / Gloor, S.L. / Hastings, G. / Rana, S. / Rasor, K. / Sturgis, H.L. / Voegtli, W.C. / Vigers, G. / ...Authors: Wenglowsky, S. / Ren, L. / Grina, J. / Hansen, J.D. / Laird, E.R. / Moreno, D. / Dinkel, V. / Gloor, S.L. / Hastings, G. / Rana, S. / Rasor, K. / Sturgis, H.L. / Voegtli, W.C. / Vigers, G. / Willis, B. / Mathieu, S. / Rudolph, J.
History
DepositionFeb 26, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 9, 2014Provider: repository / Type: Initial release
Revision 1.1May 7, 2014Group: Database references
Revision 1.2Feb 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)71,2804
Polymers70,4352
Non-polymers8452
Water00
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6402
Polymers35,2181
Non-polymers4221
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6402
Polymers35,2181
Non-polymers4221
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)107.971, 107.971, 151.669
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: 35217.633 Da / Num. of mol.: 2 / Fragment: protein kinase domain (UNP residues 432-726)
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-2VX / N-{2,4-difluoro-3-[methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}propane-1-sulfonamide


Mass: 422.449 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20F2N4O3S

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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: 3.14 Å3/Da / Density % sol: 60.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 9
Details: 100 mM Tris, pH 9.0, 8% PEG6000, glycerol, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jan 1, 2010
RadiationMonochromator: Confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3.4→25 Å / Num. all: 12844 / Num. obs: 12732 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.54 % / Rmerge(I) obs: 0.144 / Rsym value: 0.122 / Net I/σ(I): 9.58
Reflection shellResolution: 3.4→3.58 Å / Redundancy: 3.58 % / Rmerge(I) obs: 0.364 / Mean I/σ(I) obs: 2.5 / Num. unique all: 1822 / Rsym value: 0.364 / % possible all: 99.8

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.4→24.75 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.864 / SU B: 25.318 / SU ML: 0.392 / Cross valid method: THROUGHOUT / ESU R Free: 0.533 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25444 620 4.9 %RANDOM
Rwork0.19489 ---
obs0.1978 12077 98.48 %-
all-12844 --
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: 73.842 Å2
Baniso -1Baniso -2Baniso -3
1--0.74 Å2-0 Å20 Å2
2---0.74 Å2-0 Å2
3---1.47 Å2
Refinement stepCycle: LAST / Resolution: 3.4→24.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4332 0 58 0 4390
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0194489
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0831.9726067
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0925538
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.9823.744195
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.71115817
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7661528
X-RAY DIFFRACTIONr_chiral_restr0.080.2660
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0213361
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_it2.4657.3582161
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.36211.0242696
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.1417.3562326
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined7.78560.5827010
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: 3.4→3.487 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.408 47 -
Rwork0.284 847 -
obs--99.44 %

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