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- PDB-9bfb: Crystal structure of BRAF kinase domain with PF-07284890 -

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Basic information

Entry
Database: PDB / ID: 9bfb
TitleCrystal structure of BRAF kinase domain with PF-07284890
ComponentsSerine/threonine-protein kinase B-raf
KeywordsSIGNALING PROTEIN / Braf inhibitor / kinase domain
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 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 / cellular response to calcium ion / ERK1 and ERK2 cascade / substrate adhesion-dependent cell spreading / cellular response to nerve growth factor stimulus / thymus development / long-term synaptic potentiation / animal organ morphogenesis / RAF activation / Spry regulation of FGF signaling / 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 / positive regulation of peptidyl-serine phosphorylation / presynapse / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / T cell differentiation in thymus / 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 / positive regulation of gene expression / protein-containing complex binding / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / 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
Similarity search - Domain/homology
: / DI(HYDROXYETHYL)ETHER / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsMou, T.-C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Identification of the Clinical Candidate PF-07284890 ( ARRY-461 ), a Highly Potent and Brain Penetrant BRAF Inhibitor for the Treatment of Cancer.
Authors: Ren, L. / Moreno, D. / Baer, B.R. / Barbour, P. / Bettendorf, T. / Bouhana, K. / Brown, K. / Brown, S.A. / Fell, J.B. / Hartley, D.P. / Hicken, E.J. / Laird, E.R. / Lee, P. / McCown, J. / ...Authors: Ren, L. / Moreno, D. / Baer, B.R. / Barbour, P. / Bettendorf, T. / Bouhana, K. / Brown, K. / Brown, S.A. / Fell, J.B. / Hartley, D.P. / Hicken, E.J. / Laird, E.R. / Lee, P. / McCown, J. / Otten, J.N. / Prigaro, B. / Wallace, R. / Kahn, D.
History
DepositionApr 17, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8554
Polymers33,2001
Non-polymers6553
Water4,396244
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)97.609, 97.609, 69.311
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z
Components on special symmetry positions
IDModelComponents
11A-801-

PEG

21A-1123-

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: 33200.359 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: unidentified baculovirus
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-A1AN9 / N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]-4-fluorophenyl}-3-fluoropropane-1-sulfonamide


Mass: 456.894 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19ClF2N4O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 244 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.87 Å3/Da / Density % sol: 57.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7 / Details: 100mM Hepes pH 7.0, 15 % PEG 8K, 10% Tacsimate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.54 Å
DetectorType: DECTRIS EIGER R 1M / Detector: PIXEL / Date: Mar 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.92→29.02 Å / Num. obs: 29350 / % possible obs: 99.85 % / Redundancy: 9 % / Biso Wilson estimate: 23.39 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.027 / Rrim(I) all: 0.081 / Net I/σ(I): 17.6
Reflection shellResolution: 1.92→1.97 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.566 / Mean I/σ(I) obs: 3 / Num. unique obs: 1965 / CC1/2: 0.878 / Rpim(I) all: 0.22 / Rrim(I) all: 0.609 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
DENZOdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.92→29.02 Å / SU ML: 0.1846 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.5651
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1888 2006 6.84 %
Rwork0.1639 27307 -
obs0.1656 29313 99.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.06 Å2
Refinement stepCycle: LAST / Resolution: 1.92→29.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2164 0 43 244 2451
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00762314
X-RAY DIFFRACTIONf_angle_d0.93743134
X-RAY DIFFRACTIONf_chiral_restr0.0619341
X-RAY DIFFRACTIONf_plane_restr0.0087396
X-RAY DIFFRACTIONf_dihedral_angle_d16.4938884
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.92-1.970.26871400.22271921X-RAY DIFFRACTION99.81
1.97-2.020.22171380.19831939X-RAY DIFFRACTION99.95
2.02-2.080.21331420.19481915X-RAY DIFFRACTION100
2.08-2.150.19331420.18081926X-RAY DIFFRACTION99.95
2.15-2.230.23481460.16821962X-RAY DIFFRACTION99.91
2.23-2.320.20911420.16431910X-RAY DIFFRACTION99.9
2.32-2.420.19691400.1781931X-RAY DIFFRACTION100
2.42-2.550.22091440.1691957X-RAY DIFFRACTION99.95
2.55-2.710.20551430.17491930X-RAY DIFFRACTION100
2.71-2.920.21411440.16511959X-RAY DIFFRACTION100
2.92-3.210.17131440.15991935X-RAY DIFFRACTION99.86
3.21-3.670.19341490.13911975X-RAY DIFFRACTION99.81
3.68-4.620.14681440.13951979X-RAY DIFFRACTION99.48
4.63-29.020.16861480.17282068X-RAY DIFFRACTION99.95
Refinement TLS params.Method: refined / Origin x: 45.9383290977 Å / Origin y: -12.0944918463 Å / Origin z: -24.0167605187 Å
111213212223313233
T0.131658341225 Å20.0136802981476 Å20.00462536281568 Å2-0.078894020966 Å2-0.00678057426482 Å2--0.150364532611 Å2
L1.32113850271 °20.260799879414 °20.0310967053427 °2-1.58868896373 °20.14242007596 °2--2.79546576059 °2
S0.0481106441438 Å °0.096562889923 Å °-0.0724766506553 Å °-0.116123784211 Å °-0.0232999086061 Å °0.098379571436 Å °0.053281130521 Å °-0.0929485816129 Å °-0.0255593034557 Å °
Refinement TLS groupSelection details: (chain 'A' and resid 448 through 721)

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