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- PDB-5hid: BRAF Kinase domain b3aC loop deletion mutant in complex with AZ628 -

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Basic information

Entry
Database: PDB / ID: 5hid
TitleBRAF Kinase domain b3aC loop deletion mutant in complex with AZ628
ComponentsSerine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / 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 / 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 / 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 / positive regulation of peptidyl-serine phosphorylation / T cell differentiation in thymus / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / scaffold protein binding / negative regulation of neuron apoptotic process / Ras protein signal transduction / 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) / 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-B1E / DI(HYDROXYETHYL)ETHER / Serine/threonine-protein kinase B-raf
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsWhalen, D.M. / Foster, S.A. / Ozen, A. / Wongchenko, M. / Yin, J. / Schaefer, G. / Mayfield, J. / Chmielecki, J. / Stephens, P. / Albacker, L. ...Whalen, D.M. / Foster, S.A. / Ozen, A. / Wongchenko, M. / Yin, J. / Schaefer, G. / Mayfield, J. / Chmielecki, J. / Stephens, P. / Albacker, L. / Yan, Y. / Song, K. / Hatzivassiliou, G. / Eigenbrot, C. / Yu, C. / Shaw, A.S. / Manning, G. / Skelton, N.J. / Hymowitz, S.G. / Malek, S.
CitationJournal: Cancer Cell / Year: 2016
Title: Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.
Authors: Foster, S.A. / Whalen, D.M. / Ozen, A. / Wongchenko, M.J. / Yin, J. / Yen, I. / Schaefer, G. / Mayfield, J.D. / Chmielecki, J. / Stephens, P.J. / Albacker, L.A. / Yan, Y. / Song, K. / ...Authors: Foster, S.A. / Whalen, D.M. / Ozen, A. / Wongchenko, M.J. / Yin, J. / Yen, I. / Schaefer, G. / Mayfield, J.D. / Chmielecki, J. / Stephens, P.J. / Albacker, L.A. / Yan, Y. / Song, K. / Hatzivassiliou, G. / Eigenbrot, C. / Yu, C. / Shaw, A.S. / Manning, G. / Skelton, N.J. / Hymowitz, S.G. / Malek, S.
History
DepositionJan 11, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 20, 2016Group: Database references
Revision 1.2Aug 3, 2016Group: Structure summary
Revision 1.3Sep 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

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)65,8336
Polymers64,7182
Non-polymers1,1154
Water2,036113
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2310 Å2
ΔGint-3 kcal/mol
Surface area24330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.710, 100.400, 108.890
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: 32359.061 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Escherichia coli (E. coli)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-B1E / 3-(2-cyanopropan-2-yl)-N-{4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}benzamide


Mass: 451.520 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H25N5O2
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C4H10O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 113 / 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: 2.17 Å3/Da / Density % sol: 43.23 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / Details: 20% PEG 3350, and 0.2M Potassium Nitrate

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 22, 2015
RadiationMonochromator: Liquid nitrogen-cooled double crystal, non fixed exit slit. Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.5→47.86 Å / Biso Wilson estimate: 44.14 Å2
Reflection shellResolution: 2.5→2.65 Å / Mean I/σ(I) obs: 1.52 / % possible all: 71.3

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5HI2 (partially refined)

5hi2


Resolution: 2.5→47.86 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.9204 / SU R Cruickshank DPI: 1.029 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.296 / SU Rfree Blow DPI: 0.336 / SU Rfree Cruickshank DPI: 0.336
RfactorNum. reflection% reflectionSelection details
Rfree0.279 979 5.11 %RANDOM
Rwork0.2341 ---
obs0.2364 19162 98.25 %-
Displacement parametersBiso mean: 41.46 Å2
Baniso -1Baniso -2Baniso -3
1--6.5714 Å20 Å20 Å2
2--6.4475 Å20 Å2
3---0.1239 Å2
Refine analyzeLuzzati coordinate error obs: 0.364 Å
Refinement stepCycle: LAST / Resolution: 2.5→47.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4235 0 82 113 4430
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0114410HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.25943HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1592SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes107HARMONIC2
X-RAY DIFFRACTIONt_gen_planes635HARMONIC5
X-RAY DIFFRACTIONt_it4410HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion4.26
X-RAY DIFFRACTIONt_other_torsion18.1
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion549SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5011SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.63 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.3136 128 4.95 %
Rwork0.2048 2460 -
all0.2101 2588 -
obs--98.25 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.13010.0239-0.01171.6233-0.12290.43610.04080.0859-0.1083-0.17-0.0175-0.19850.11260.0896-0.0233-0.13220.0079-0.0244-0.1391-0.04350.10489.5452-10.6545-13.9163
22.0807-0.0521-0.52482.4976-0.12891.6135-0.0431-0.041-0.1530.04640.00260.10870.139-0.0320.0405-0.149-0.0257-0.0007-0.13540.00770.053-8.2205-20.6748-9.2886
32.22660.1730.1251.91590.52730.90470.05440.0460.0226-0.04890.03310.2053-0.1406-0.0865-0.0875-0.1157-0.00230.0369-0.17590.03480.1012-1.933610.6641-13.9117
42.10840.13590.50181.98870.22441.5324-0.1113-0.01040.1633-0.01640.0305-0.1767-0.25530.15740.0808-0.1346-0.0428-0.001-0.1587-0.0030.058914.803521.5233-10.4551
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|454 - A|560 }
2X-RAY DIFFRACTION2{ A|561 - A|722 }
3X-RAY DIFFRACTION3{ B|454 - B|560 }
4X-RAY DIFFRACTION4{ B|561 - B|722 }

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