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- PDB-6fek: Oncogenic point mutation of RET receptor tyrosine kinase -

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Basic information

Entry
Database: PDB / ID: 6fek
TitleOncogenic point mutation of RET receptor tyrosine kinase
ComponentsProto-oncogene tyrosine-protein kinase receptor Ret
KeywordsONCOPROTEIN / tyrosine kinase / oncogene / mutation
Function / homology
Function and homology information


Peyer's patch morphogenesis / GDF15-GFRAL signaling pathway / positive regulation of metanephric glomerulus development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / posterior midgut development / membrane protein proteolysis / Formation of the ureteric bud ...Peyer's patch morphogenesis / GDF15-GFRAL signaling pathway / positive regulation of metanephric glomerulus development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / posterior midgut development / membrane protein proteolysis / Formation of the ureteric bud / positive regulation of neuron maturation / neuron cell-cell adhesion / Formation of the nephric duct / enteric nervous system development / innervation / plasma membrane protein complex / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / neuron maturation / positive regulation of cell adhesion mediated by integrin / neural crest cell migration / ureteric bud development / regulation of axonogenesis / response to pain / homophilic cell adhesion via plasma membrane adhesion molecules / RET signaling / positive regulation of cell size / regulation of cell adhesion / cellular response to retinoic acid / transmembrane receptor protein tyrosine kinase activity / NPAS4 regulates expression of target genes / axon guidance / : / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / positive regulation of neuron projection development / cell surface receptor protein tyrosine kinase signaling pathway / MAPK cascade / signaling receptor activity / retina development in camera-type eye / protein tyrosine kinase activity / RAF/MAP kinase cascade / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / positive regulation of MAPK cascade / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / positive regulation of cell migration / protein phosphorylation / response to xenobiotic stimulus / axon / neuronal cell body / dendrite / calcium ion binding / positive regulation of gene expression / positive regulation of DNA-templated transcription / signal transduction / ATP binding / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / : / RET Cadherin like domain 1 / RET Cadherin like domain 3 / RET Cadherin like domain 4 / RET, Cysteine Rich Domain / Cadherin domain ...Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / : / RET Cadherin like domain 1 / RET Cadherin like domain 3 / RET Cadherin like domain 4 / RET, Cysteine Rich Domain / Cadherin domain / Cadherin-like / Cadherins domain profile. / Cadherin-like superfamily / : / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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
ADENOSINE / FORMIC ACID / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsMcDonald, N.Q. / Kohno, T.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Francis Crick InstituteFC001115 United Kingdom
CitationJournal: Nat Commun / Year: 2018
Title: A secondary RET mutation in the activation loop conferring resistance to vandetanib.
Authors: Nakaoku, T. / Kohno, T. / Araki, M. / Niho, S. / Chauhan, R. / Knowles, P.P. / Tsuchihara, K. / Matsumoto, S. / Shimada, Y. / Mimaki, S. / Ishii, G. / Ichikawa, H. / Nagatoishi, S. / ...Authors: Nakaoku, T. / Kohno, T. / Araki, M. / Niho, S. / Chauhan, R. / Knowles, P.P. / Tsuchihara, K. / Matsumoto, S. / Shimada, Y. / Mimaki, S. / Ishii, G. / Ichikawa, H. / Nagatoishi, S. / Tsumoto, K. / Okuno, Y. / Yoh, K. / McDonald, N.Q. / Goto, K.
History
DepositionJan 2, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 28, 2018Provider: repository / Type: Initial release
Revision 1.1May 2, 2018Group: Data collection / Category: reflns / reflns_shell
Item: _reflns.pdbx_Rpim_I_all / _reflns_shell.pdbx_Rpim_I_all
Revision 1.2Oct 16, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Proto-oncogene tyrosine-protein kinase receptor Ret
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7115
Polymers34,3061
Non-polymers4054
Water59433
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1010 Å2
ΔGint3 kcal/mol
Surface area14350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.901, 50.901, 242.515
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Proto-oncogene tyrosine-protein kinase receptor Ret / Cadherin family member 12 / Proto-oncogene c-Ret


Mass: 34305.684 Da / Num. of mol.: 1 / Mutation: S904F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RET, CDHF12, CDHR16, PTC, RET51 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07949, receptor protein-tyrosine kinase
#2: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: CH2O2
#3: Chemical ChemComp-ADN / ADENOSINE


Mass: 267.241 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H13N5O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.36 Å3/Da / Density % sol: 47.84 % / Description: plates
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 4.4
Details: 3.4 M sodium formate, and 0.1 M sodium acetate pH 4.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 29, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.08→48.5 Å / Num. obs: 27003 / % possible obs: 98.5 % / Redundancy: 24.5 % / Biso Wilson estimate: 28.3 Å2 / CC1/2: 0.998 / Rpim(I) all: 0.046 / Net I/σ(I): 12.8
Reflection shellResolution: 2.08→2.19 Å / Redundancy: 25.5 % / Mean I/σ(I) obs: 2 / Num. unique obs: 1364 / CC1/2: 0.641 / Rpim(I) all: 0.34 / % possible all: 97

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→46.934 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 23.62
RfactorNum. reflection% reflection
Rfree0.2441 1364 5.05 %
Rwork0.2007 --
obs0.2029 27002 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.3→46.934 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2276 0 28 33 2337
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032369
X-RAY DIFFRACTIONf_angle_d0.5823217
X-RAY DIFFRACTIONf_dihedral_angle_d16.0511401
X-RAY DIFFRACTIONf_chiral_restr0.043356
X-RAY DIFFRACTIONf_plane_restr0.003405
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.38220.2871390.2792558X-RAY DIFFRACTION100
2.3822-2.47760.3471400.26812591X-RAY DIFFRACTION100
2.4776-2.59040.27671370.25522535X-RAY DIFFRACTION100
2.5904-2.72690.27341340.24862566X-RAY DIFFRACTION100
2.7269-2.89770.28231310.22822568X-RAY DIFFRACTION100
2.8977-3.12140.27151420.23832571X-RAY DIFFRACTION100
3.1214-3.43550.24691330.20382584X-RAY DIFFRACTION100
3.4355-3.93240.25861300.18472542X-RAY DIFFRACTION99
3.9324-4.95350.16221360.14912559X-RAY DIFFRACTION100
4.9535-46.94330.23951420.17692564X-RAY DIFFRACTION100

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