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- PDB-7ju5: Structure of RET protein tyrosine kinase in complex with pralsetinib -

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Basic information

Entry
Database: PDB / ID: 7ju5
TitleStructure of RET protein tyrosine kinase in complex with pralsetinib
ComponentsProto-oncogene tyrosine-protein kinase receptor Ret
KeywordsTransferase/Transferase inhibitor / oncogene / RET / Tyrosine Kinase / ATP-binding / Thyroid cancer / Non small cell lung cancer / pralsetinib / Transferase-Transferase inhibitor complex / TRANSFERASE
Function / homology
Function and homology information


GDF15-GFRAL signaling pathway / Peyer's patch morphogenesis / 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 / positive regulation of peptidyl-serine phosphorylation of STAT protein / membrane protein proteolysis ...GDF15-GFRAL signaling pathway / Peyer's patch morphogenesis / 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 / positive regulation of peptidyl-serine phosphorylation of STAT protein / 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 / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of cell adhesion mediated by integrin / ureteric bud development / neural crest cell migration / 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 / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / axon guidance / receptor protein-tyrosine kinase / : / positive regulation of neuron projection development / MAPK cascade / retina development in camera-type eye / signaling receptor activity / RAF/MAP kinase cascade / protein tyrosine 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 / response to xenobiotic stimulus / protein phosphorylation / 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 / 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 / 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 / Pralsetinib / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9 Å
AuthorsTerzyan, S.S. / Shen, T. / Wu, J. / Mooers, B.H.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)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 ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)72,6688
Polymers71,4162
Non-polymers1,2516
Water4,756264
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3830 Å2
ΔGint-13 kcal/mol
Surface area25080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.449, 80.329, 79.840
Angle α, β, γ (deg.)90.000, 100.250, 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 1 BOLD-2017 (butterflies/moths)
References: UniProt: P07949, receptor protein-tyrosine kinase
#2: Chemical ChemComp-Q4J / Pralsetinib / BLU-667 / trans-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide


Mass: 533.600 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H32FN9O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#3: Chemical
ChemComp-FMT / FORMIC ACID


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


Mass: 18.015 Da / Num. of mol.: 264 / 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: 48.93 % / Description: Transparent small crystals.
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 21-30% PEG3350 0.1M Na Citrate pH 5.5 / Temp details: Room temperature

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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: May 11, 2019 / Details: Flat bent Colimator Rh covered
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→100 Å / Num. obs: 47291 / % possible obs: 95.2 % / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Biso Wilson estimate: 26.38 Å2 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.039 / Rrim(I) all: 0.073 / Χ2: 1.022 / Net I/σ(I): 17.18
Reflection shellResolution: 1.9→1.93 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.532 / Mean I/σ(I) obs: 2 / Num. unique obs: 2337 / CC1/2: 0.86 / Rpim(I) all: 0.383 / Rrim(I) all: 0.66 / Χ2: 1.27 / % possible all: 89.4

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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: 1.9→78.57 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.934 / SU B: 5.191 / SU ML: 0.143 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.169 / ESU R Free: 0.164 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2475 2389 5.1 %RANDOM
Rwork0.188 ---
obs0.191 44787 94.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 128.44 Å2 / Biso mean: 36.413 Å2 / Biso min: 15.09 Å2
Baniso -1Baniso -2Baniso -3
1-2.31 Å20 Å20.83 Å2
2---0.89 Å2-0 Å2
3----1.62 Å2
Refinement stepCycle: final / Resolution: 1.9→78.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4623 0 90 264 4977
Biso mean--31.01 40.34 -
Num. residues----577
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0194966
X-RAY DIFFRACTIONr_bond_other_d0.0010.024835
X-RAY DIFFRACTIONr_angle_refined_deg1.8231.996715
X-RAY DIFFRACTIONr_angle_other_deg0.9093.00411143
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8735609
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.17823.333216
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.93115912
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.6841539
X-RAY DIFFRACTIONr_chiral_restr0.1130.2712
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0215565
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021148
LS refinement shellResolution: 1.9→1.947 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.423 161 -
Rwork0.442 3097 -
obs--88.46 %

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