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- PDB-5ita: Crystal Structure of BRAF Kinase Domain Bound to AZ-VEM -

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Basic information

Entry
Database: PDB / ID: 5ita
TitleCrystal Structure of BRAF Kinase Domain Bound to AZ-VEM
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / transferase / kinase and inhibitor complex / 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 / response to cAMP / positive regulation of stress fiber assembly / 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-6DC / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsWu, Y. / Gavathiotis, E.
CitationJournal: Cancer Cell / Year: 2016
Title: An integrated model of RAF inhibitor action predicts inhibitor activity against oncogenic BRAF signaling
Authors: Karoulia, Z. / Wu, Y. / Ahmed, T.A. / Qisheng, X. / Bollard, J. / Krepler, C. / Wu, X. / Zhang, C. / Bollag, G. / Herlym, M. / Fagin, J.A. / Lujambio, A. / Gavathiotis, E. / Poulikakos, P.I.
History
DepositionMar 16, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)68,2584
Polymers67,4632
Non-polymers7952
Water1,78399
1
A: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1292
Polymers33,7321
Non-polymers3971
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1292
Polymers33,7321
Non-polymers3971
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2520 Å2
ΔGint-4 kcal/mol
Surface area22450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.105, 103.817, 110.567
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: 33731.652 Da / Num. of mol.: 2 / Fragment: residues 448-723
Mutation: I543A, I544S, I551K, Q562R, L588N, K630S, F667E, Y673S, A688R, L706S, Q709R, S713E, L716E, S720E, P722S, K723G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-6DC / N-{2-cyano-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}propane-1-sulfonamide


Mass: 397.451 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19N5O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 99 / 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: 2.22 Å3/Da / Density % sol: 44.5 %
Crystal growTemperature: 291.1 K / Method: vapor diffusion, sitting drop / Details: PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9797 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Oct 12, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9797 Å / Relative weight: 1
ReflectionResolution: 1.949→50 Å / Num. obs: 44542 / % possible obs: 99.7 % / Redundancy: 7.2 % / Net I/σ(I): 26.9

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3OG7

3og7


Resolution: 1.95→34.73 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.86
RfactorNum. reflection% reflection
Rfree0.244 2302 5.18 %
Rwork0.195 --
obs0.197 44423 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.95→34.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4022 0 56 99 4177
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094159
X-RAY DIFFRACTIONf_angle_d1.0025607
X-RAY DIFFRACTIONf_dihedral_angle_d17.3762520
X-RAY DIFFRACTIONf_chiral_restr0.058607
X-RAY DIFFRACTIONf_plane_restr0.006709
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9491-1.99150.28841420.24972575X-RAY DIFFRACTION99
1.9915-2.03780.28471450.23162605X-RAY DIFFRACTION100
2.0378-2.08880.27931720.21142566X-RAY DIFFRACTION100
2.0888-2.14520.23381380.21592604X-RAY DIFFRACTION100
2.1452-2.20840.26771450.19912596X-RAY DIFFRACTION100
2.2084-2.27960.21571660.19882599X-RAY DIFFRACTION100
2.2796-2.36110.27241380.18922634X-RAY DIFFRACTION100
2.3611-2.45560.25861310.20142627X-RAY DIFFRACTION100
2.4556-2.56730.25631310.21482618X-RAY DIFFRACTION100
2.5673-2.70260.26891420.20952641X-RAY DIFFRACTION100
2.7026-2.87190.28311270.21822650X-RAY DIFFRACTION100
2.8719-3.09350.23081410.22242644X-RAY DIFFRACTION100
3.0935-3.40460.2521370.20442673X-RAY DIFFRACTION100
3.4046-3.89660.2451790.18712637X-RAY DIFFRACTION100
3.8966-4.90710.19311370.15392715X-RAY DIFFRACTION100
4.9071-34.73750.24841310.1872737X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: 26.1936 Å / Origin y: -2.403 Å / Origin z: -7.1197 Å
111213212223313233
T0.1999 Å20.0006 Å20.0241 Å2-0.2113 Å20.0294 Å2--0.1998 Å2
L0.7066 °20.2305 °20.4459 °2-1.9812 °21.5434 °2--2.2141 °2
S0.027 Å °-0.1256 Å °-0.0622 Å °0.2462 Å °0.0266 Å °-0.066 Å °0.3083 Å °-0.0881 Å °-0.0541 Å °
Refinement TLS groupSelection details: ALL

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