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- PDB-3d4q: Pyrazole-based inhibitors of B-Raf kinase -

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Basic information

Entry
Database: PDB / ID: 3d4q
TitlePyrazole-based inhibitors of B-Raf kinase
ComponentsB-Raf proto-oncogene serine/threonine-protein kinase
KeywordsTRANSFERASE / Kinase / ATP-binding / Cardiomyopathy / Disease mutation / Metal-binding / Nucleotide-binding / Phorbol-ester binding / Phosphoprotein / Proto-oncogene / Serine/threonine-protein kinase / Zinc-finger
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 / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...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 / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / negative regulation of fibroblast migration / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / positive regulation of axonogenesis / regulation of T cell differentiation / mitogen-activated protein kinase kinase binding / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / positive regulation of axon regeneration / stress fiber assembly / face development / MAP kinase kinase activity / synaptic vesicle exocytosis / thyroid gland development / somatic stem cell population maintenance / MAP kinase kinase kinase activity / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / response to cAMP / positive regulation of peptidyl-serine phosphorylation / positive regulation of stress fiber assembly / positive regulation of substrate adhesion-dependent cell spreading / ERK1 and ERK2 cascade / substrate adhesion-dependent cell spreading / cellular response to calcium ion / thymus development / animal organ morphogenesis / RAF activation / cellular response to nerve growth factor stimulus / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / response to peptide hormone / centriolar satellite / long-term synaptic potentiation / epidermal growth factor receptor signaling pathway / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / 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 / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / postsynapse / protein kinase activity / neuron projection / ciliary basal body / cilium / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / calcium ion binding / positive regulation of gene expression / protein-containing complex binding / negative regulation of apoptotic process / glutamatergic synapse / mitochondrion / zinc ion binding
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 / 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-SM5 / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.8 Å
AuthorsMorales, T. / Vigers, G.P.A. / Brandhuber, B.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Potent and selective pyrazole-based inhibitors of B-Raf kinase.
Authors: Hansen, J.D. / Grina, J. / Newhouse, B. / Welch, M. / Topalov, G. / Littman, N. / Callejo, M. / Gloor, S. / Martinson, M. / Laird, E. / Brandhuber, B.J. / Vigers, G. / Morales, T. / ...Authors: Hansen, J.D. / Grina, J. / Newhouse, B. / Welch, M. / Topalov, G. / Littman, N. / Callejo, M. / Gloor, S. / Martinson, M. / Laird, E. / Brandhuber, B.J. / Vigers, G. / Morales, T. / Woessner, R. / Randolph, N. / Lyssikatos, J. / Olivero, A.
History
DepositionMay 14, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Feb 21, 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: B-Raf proto-oncogene serine/threonine-protein kinase
B: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,1824
Polymers70,4352
Non-polymers7472
Water41423
1
A: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5912
Polymers35,2181
Non-polymers3731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: B-Raf proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5912
Polymers35,2181
Non-polymers3731
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)100.343, 100.343, 162.536
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein B-Raf proto-oncogene serine/threonine-protein kinase / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 35217.633 Da / Num. of mol.: 2 / Fragment: Residues 432-726
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Cell line (production host): Hi-5 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SM5 / (1E)-5-(1-piperidin-4-yl-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one oxime


Mass: 373.451 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H23N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 2.9 Å3/Da / Density % sol: 57.65 %
Crystal growTemperature: 285 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 5% PEG 3350 0.1M Tris 10% Tacsimate, pH 7.8, VAPOR DIFFUSION, HANGING DROP, temperature 285K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 0.9 Å
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. all: 20683 / Num. obs: 20661 / % possible obs: 88.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2.5 / Redundancy: 8.8 % / Biso Wilson estimate: 51.8 Å2 / Rmerge(I) obs: 0.074
Reflection shellResolution: 2.8→2.91 Å / Redundancy: 8.9 % / Rmerge(I) obs: 0.408 / Mean I/σ(I) obs: 3.5 / Num. unique all: 2002 / % possible all: 64.4

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT3.005data extraction
ADSCQuantumdata collection
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementResolution: 2.8→30 Å / σ(F): 0 / σ(I): 2.5 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.25 1002 4.7 %Random
Rwork0.216 ---
all-20683 --
obs-20642 97.8 %-
Displacement parametersBiso mean: 57.621 Å2
Baniso -1Baniso -2Baniso -3
1--0.189 Å20 Å20 Å2
2---0.189 Å20 Å2
3---0.378 Å2
Refinement stepCycle: LAST / Resolution: 2.8→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4214 0 56 23 4293
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.02
X-RAY DIFFRACTIONc_angle_d1.657
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2water_rep.param
X-RAY DIFFRACTION3ion.param
X-RAY DIFFRACTION4AR00384000.par

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