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- PDB-6i82: Crystal structure of partially phosphorylated RET V804M tyrosine ... -

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Basic information

Entry
Database: PDB / ID: 6i82
TitleCrystal structure of partially phosphorylated RET V804M tyrosine kinase domain complexed with PDD00018412
ComponentsProto-oncogene tyrosine-protein kinase receptor Ret
KeywordsONCOPROTEIN / inhibitor / kinase / proto-oncogene
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 / Formation of the ureteric bud / membrane protein proteolysis ...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 / Formation of the ureteric bud / membrane protein proteolysis / Formation of the nephric duct / enteric nervous system development / neuron cell-cell adhesion / plasma membrane protein complex / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of cell adhesion mediated by integrin / neural crest cell migration / ureteric bud development / regulation of axonogenesis / response to pain / homophilic cell-cell adhesion / RET signaling / positive regulation of cell size / regulation of cell adhesion / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of neuron projection development / receptor protein-tyrosine kinase / signaling receptor activity / MAPK cascade / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / endosome membrane / positive regulation of cell migration / axon / 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 / 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
FORMIC ACID / Chem-H6W / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsBurschowsky, D. / Seewooruthun, C. / Bayliss, R. / Carr, M.D. / Echalier, A. / Jordan, A.M.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Cancer Research UKGrant C480/A11411 United Kingdom
Cancer Research UKC5759/A17098 United Kingdom
Cancer Research UKC1362/A20263 United Kingdom
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery and Optimization of wt-RET/KDR-Selective Inhibitors of RETV804MKinase.
Authors: Newton, R. / Waszkowycz, B. / Seewooruthun, C. / Burschowsky, D. / Richards, M. / Hitchin, S. / Begum, H. / Watson, A. / French, E. / Hamilton, N. / Jones, S. / Lin, L.Y. / Waddell, I. / ...Authors: Newton, R. / Waszkowycz, B. / Seewooruthun, C. / Burschowsky, D. / Richards, M. / Hitchin, S. / Begum, H. / Watson, A. / French, E. / Hamilton, N. / Jones, S. / Lin, L.Y. / Waddell, I. / Echalier, A. / Bayliss, R. / Jordan, A.M. / Ogilvie, D.
History
DepositionNov 19, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 11, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)73,35625
Polymers71,6412
Non-polymers1,71523
Water3,819212
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5950 Å2
ΔGint-15 kcal/mol
Surface area24820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.675, 80.336, 79.740
Angle α, β, γ (deg.)90.00, 99.87, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 35820.277 Da / Num. of mol.: 2 / Mutation: V804M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RET, CDHF12, CDHR16, PTC, RET51 / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: P07949, receptor protein-tyrosine kinase

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Non-polymers , 5 types, 235 molecules

#2: Chemical ChemComp-H6W / ~{N}-[3-(1,3-benzodioxol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-~{N}',~{N}'-dimethyl-propane-1,3-diamine


Mass: 339.392 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H21N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: CH2O2
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 212 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.23 Å3/Da / Density % sol: 44.9 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1 M sodium citrate pH 4.5-5.5, 2.0 M sodium formate drop size 500 nl + 500 nl RET at 3 mg/ml in 20 mM Tris pH 8.0, 100 mM NaCl, 1 mM DTT
PH range: 4.5-5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 14, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.05→45.89 Å / Num. obs: 38208 / % possible obs: 96.4 % / Redundancy: 3.1 % / CC1/2: 1 / Rmerge(I) obs: 0.08 / Net I/σ(I): 7.5
Reflection shellResolution: 2.05→2.11 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 2324 / CC1/2: 0.73 / % possible all: 75

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Processing

Software
NameClassification
GDAdata collection
XDSdata reduction
XDSdata scaling
PHASERphasing
REFMACrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2IVS

2ivs


Resolution: 2.05→45.89 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.935 / SU B: 5.999 / SU ML: 0.153 / Cross valid method: THROUGHOUT / ESU R: 0.201 / ESU R Free: 0.178 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22928 1876 4.9 %RANDOM
Rwork0.17601 ---
obs0.17871 36312 96.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 33.246 Å2
Baniso -1Baniso -2Baniso -3
1-2.58 Å20 Å21.11 Å2
2---1.03 Å20 Å2
3----1.83 Å2
Refinement stepCycle: 1 / Resolution: 2.05→45.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4569 0 116 212 4897
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0134772
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174561
X-RAY DIFFRACTIONr_angle_refined_deg1.6451.6456394
X-RAY DIFFRACTIONr_angle_other_deg1.281.58310561
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4315562
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.95621.328241
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.77215869
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.7421536
X-RAY DIFFRACTIONr_chiral_restr0.0780.2568
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025210
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021034
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.8813.2362263
X-RAY DIFFRACTIONr_mcbond_other2.8823.2372264
X-RAY DIFFRACTIONr_mcangle_it4.2174.8352820
X-RAY DIFFRACTIONr_mcangle_other4.2174.8372821
X-RAY DIFFRACTIONr_scbond_it3.8543.7482509
X-RAY DIFFRACTIONr_scbond_other3.8083.742480
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.8765.4083575
X-RAY DIFFRACTIONr_long_range_B_refined7.69438.0165432
X-RAY DIFFRACTIONr_long_range_B_other7.68637.9285395
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.05→2.103 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 92 -
Rwork0.309 2086 -
obs--74.51 %

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