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- PDB-4e4x: Crystal Structure of B-Raf Kinase Domain in Complex with a Dihydr... -

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Basic information

Entry
Database: PDB / ID: 4e4x
TitleCrystal Structure of B-Raf Kinase Domain in Complex with a Dihydropyrido[2,3-d]pyrimidinone-based Inhibitor
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTransferase/Transferase Inhibitor / Kinase / 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-T1Q / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.6 Å
AuthorsVoegtli, W.C. / Sturgis, H.L.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B-Raf(V600E) kinase.
Authors: Ren, L. / Ahrendt, K.A. / Grina, J. / Laird, E.R. / Buckmelter, A.J. / Hansen, J.D. / Newhouse, B. / Moreno, D. / Wenglowsky, S. / Dinkel, V. / Gloor, S.L. / Hastings, G. / Rana, S. / Rasor, ...Authors: Ren, L. / Ahrendt, K.A. / Grina, J. / Laird, E.R. / Buckmelter, A.J. / Hansen, J.D. / Newhouse, B. / Moreno, D. / Wenglowsky, S. / Dinkel, V. / Gloor, S.L. / Hastings, G. / Rana, S. / Rasor, K. / Risom, T. / Sturgis, H.L. / Voegtli, W.C. / Mathieu, S.
History
DepositionMar 13, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 9, 2012Provider: repository / Type: Initial release
Revision 1.1May 23, 2012Group: 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

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)71,3704
Polymers70,4352
Non-polymers9352
Water00
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6852
Polymers35,2181
Non-polymers4671
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)35,6852
Polymers35,2181
Non-polymers4671
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)109.000, 109.000, 155.210
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: B-Raf (432-726)
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-T1Q / N-(2,4-difluoro-3-{2-[(3-hydroxypropyl)amino]-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl}phenyl)propane-1-sulfonamide


Mass: 467.490 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H23F2N5O4S

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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: 3.27 Å3/Da / Density % sol: 62.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 9
Details: PEG 8000, pH 9.0, 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 315 / Detector: CCD / Date: Nov 25, 2008
RadiationMonochromator: SSRL monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.6→30 Å / Num. all: 11359 / Num. obs: 10625 / % possible obs: 94.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Rmerge(I) obs: 0.116
Reflection shellResolution: 3.6→3.79 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.319 / Mean I/σ(I) obs: 2.4 / Num. unique all: 1559 / % possible all: 97

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
CNSrefinement
CNX2005refinement
MOSFLMdata reduction
SCALAdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.6→29.86 Å / Rfactor Rfree error: 0.012 / Data cutoff high absF: 4784685.35 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.315 650 6.1 %RANDOM
Rwork0.273 ---
obs0.275 10611 93.3 %-
all-10611 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 40.4767 Å2 / ksol: 0.321536 e/Å3
Displacement parametersBiso mean: 59.1 Å2
Baniso -1Baniso -2Baniso -3
1--15.14 Å20 Å20 Å2
2---15.14 Å20 Å2
3---30.29 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.55 Å0.44 Å
Luzzati d res low-5 Å
Luzzati sigma a0.57 Å0.59 Å
Refinement stepCycle: LAST / Resolution: 3.6→29.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4332 0 64 0 4396
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_dihedral_angle_d23.3
X-RAY DIFFRACTIONc_improper_angle_d0.57
X-RAY DIFFRACTIONc_mcbond_it1.621.5
X-RAY DIFFRACTIONc_mcangle_it2.992
X-RAY DIFFRACTIONc_scbond_it1.472
X-RAY DIFFRACTIONc_scangle_it2.622.5
Refine LS restraints NCSNCS model details: CONSTR
LS refinement shellResolution: 3.6→3.83 Å / Rfactor Rfree error: 0.033 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.338 105 6 %
Rwork0.319 1656 -
obs--95.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paraprotein.top
X-RAY DIFFRACTION2AR00462087.parAR00462087.top

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