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- PDB-7ju6: Structure of RET protein tyrosine kinase in complex with selpercatinib -

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Basic information

Entry
Database: PDB / ID: 7ju6
TitleStructure of RET protein tyrosine kinase in complex with selpercatinib
ComponentsProto-oncogene tyrosine-protein kinase receptor Ret
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / oncogene / RET / Tyrisine Kinase / ATP binding / Thyroid cancer / Non small cell lung cancer / LOXO-292 / selpercatinib / Transferase-Transferase inhibitor complex
Function / homology
Function and homology information


glial cell-derived neurotrophic factor receptor signaling pathway / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / lymphocyte migration into lymphoid organs / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / positive regulation of neuron maturation ...glial cell-derived neurotrophic factor receptor signaling pathway / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / lymphocyte migration into lymphoid organs / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / positive regulation of neuron maturation / neuron cell-cell adhesion / enteric nervous system development / innervation / 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 / response to pain / regulation of axonogenesis / homophilic cell adhesion via plasma membrane adhesion molecules / positive regulation of cell size / RET signaling / regulation of cell adhesion / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / axon guidance / receptor protein-tyrosine kinase / positive regulation of neuron projection development / cell surface receptor protein tyrosine kinase signaling pathway / activation of cysteine-type endopeptidase activity involved in apoptotic process / MAPK cascade / retina development in camera-type eye / signaling receptor activity / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / early endosome / endosome membrane / positive regulation of cell migration / response to xenobiotic stimulus / axon / protein phosphorylation / 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 / Cadherin domain / Cadherins domain profile. / Cadherin-like ...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 / Cadherin domain / Cadherins domain profile. / Cadherin-like / Cadherin-like superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, 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
FORMIC ACID / Selpercatinib / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.06 Å
AuthorsTerzyan, S.S. / Shen, T. / Wu, J. / Mooers, B.H.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P20GM103640 United States
CitationJournal: Ann Oncol / Year: 2021
Title: Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations.
Authors: Subbiah, V. / Shen, T. / Terzyan, S.S. / Liu, X. / Hu, X. / Patel, K.P. / Hu, M. / Cabanillas, M. / Behrang, A. / Meric-Bernstam, F. / Vo, P.T.T. / Mooers, B.H.M. / Wu, J.
History
DepositionAug 19, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 11, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 27, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Oct 18, 2023Group: 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

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


Theoretical massNumber of molelcules
Total (without water)72,6989
Polymers71,4162
Non-polymers1,2817
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3920 Å2
ΔGint-18 kcal/mol
Surface area25390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.621, 79.975, 79.839
Angle α, β, γ (deg.)90.000, 100.090, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 35708.234 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RET, CDHF12, CDHR16, PTC, RET51 / Plasmid: PBACPAK6 / Cell line (production host): Sf21
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: P07949, receptor protein-tyrosine kinase
#2: Chemical ChemComp-Q6G / Selpercatinib / 6-(2-hydroxy-2-methylpropoxy)-4-(6-{(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile / Selpercatinib


Mass: 525.602 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H31N7O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#3: Chemical
ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: CH2O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 2.41 Å3/Da / Density % sol: 48.91 % / Description: transparent small crystals
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 21-30% PEG3350 0.1M Na Citrate pH5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 13, 2019 / Details: Rh coated collimator
RadiationMonochromator: Double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.05→100 Å / Num. obs: 37447 / % possible obs: 97.8 % / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Biso Wilson estimate: 27.09 Å2 / Rmerge(I) obs: 0.12 / Rpim(I) all: 0.077 / Rrim(I) all: 0.143 / Χ2: 0.968 / Net I/σ(I): 9.7
Reflection shellResolution: 2.05→2.12 Å / Redundancy: 3 % / Rmerge(I) obs: 0.844 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 3710 / CC1/2: 0.991 / Rpim(I) all: 0.578 / Rrim(I) all: 1.028 / Χ2: 0.925 / % possible all: 97

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
REFMAC5.8.0073phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6NEC

6nec


Resolution: 2.06→78.61 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.922 / SU B: 6.724 / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.239 / ESU R Free: 0.199 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.249 1848 5 %RANDOM
Rwork0.1964 ---
obs0.199 35183 95.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 96.76 Å2 / Biso mean: 31.034 Å2 / Biso min: 13.77 Å2
Baniso -1Baniso -2Baniso -3
1-1.24 Å2-0 Å20.01 Å2
2---0.03 Å20 Å2
3----1.14 Å2
Refinement stepCycle: final / Resolution: 2.06→78.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4622 0 93 146 4861
Biso mean--24.24 32.65 -
Num. residues----579
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0194956
X-RAY DIFFRACTIONr_angle_refined_deg1.2851.9936709
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0335612
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.74823.427213
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.9115904
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2091537
X-RAY DIFFRACTIONr_chiral_restr0.0820.2718
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213711
LS refinement shellResolution: 2.064→2.118 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 122 -
Rwork0.314 2308 -
all-2430 -
obs--85.38 %

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