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- PDB-6vhg: Crystal structure of phosphorylated RET tyrosine kinase domain co... -

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Basic information

Entry
Database: PDB / ID: 6vhg
TitleCrystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrazolo[1,5-a]pyrimidine inhibitor
ComponentsProto-oncogene tyrosine-protein kinase receptor Ret
KeywordsTransferase/Transferase Inhibitor / Inhibitor / Complex / Tyrosine kinase / catalytic domain / Transferase-Transferase Inhibitor complex
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 / 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 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 / cell surface receptor protein tyrosine kinase signaling pathway / 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 / transmembrane-ephrin receptor activity / GPI-linked 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 / MAPK cascade / signaling receptor activity / retina development in camera-type eye / RAF/MAP kinase cascade / protein tyrosine kinase activity / early endosome / 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 / 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 / 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
ACETATE ION / Chem-QX1 / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.303 Å
AuthorsLee, C.C. / Spraggon, G.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma.
Authors: Mathison, C.J.N. / Chianelli, D. / Rucker, P.V. / Nelson, J. / Roland, J. / Huang, Z. / Yang, Y. / Jiang, J. / Xie, Y.F. / Epple, R. / Bursulaya, B. / Lee, C. / Gao, M.Y. / Shaffer, J. / ...Authors: Mathison, C.J.N. / Chianelli, D. / Rucker, P.V. / Nelson, J. / Roland, J. / Huang, Z. / Yang, Y. / Jiang, J. / Xie, Y.F. / Epple, R. / Bursulaya, B. / Lee, C. / Gao, M.Y. / Shaffer, J. / Briones, S. / Sarkisova, Y. / Galkin, A. / Li, L. / Li, N. / Li, C. / Hua, S. / Kasibhatla, S. / Kinyamu-Akunda, J. / Kikkawa, R. / Molteni, V. / Tellew, J.E.
History
DepositionJan 9, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 26, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 29, 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 / _citation_author.name
Revision 1.2Oct 11, 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
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)36,5029
Polymers35,5291
Non-polymers9738
Water2,396133
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)97.815, 97.815, 143.963
Angle α, β, γ (deg.)90, 90, 120
Int Tables number182
Space group name H-MP6322

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 35528.770 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RET, CDHF12, CDHR16, PTC, RET51 / Plasmid: pFastBacHT / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07949, receptor protein-tyrosine kinase

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Non-polymers , 5 types, 141 molecules

#2: Chemical ChemComp-QX1 / 3-(3,4-dimethoxyphenyl)-N~5~-(1-methylpiperidin-4-yl)-6-phenylpyrazolo[1,5-a]pyrimidine-5,7-diamine


Mass: 458.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30N6O2
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 133 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.8 Å3/Da / Density % sol: 56.04 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 4.6 / Details: 1.8M ammonium sulfate, 0.1M sodium acetate pH 4.6

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 2, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2.3→41 Å / Num. obs: 18806 / % possible obs: 97.1 % / Redundancy: 12.7 % / Rmerge(I) obs: 0.054 / Net I/σ(I): 45.2
Reflection shellResolution: 2.3→2.35 Å / Rmerge(I) obs: 0.1 / Num. unique obs: 1167

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (3-OCT-2019)refinement
DENZOdata reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2IVU

2ivu


Resolution: 2.303→41 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.251 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.274 / SU Rfree Blow DPI: 0.207 / SU Rfree Cruickshank DPI: 0.201
RfactorNum. reflection% reflectionSelection details
Rfree0.2377 898 -RANDOM
Rwork0.2028 ---
obs0.2045 18144 97.1 %-
Displacement parametersBiso mean: 35.13 Å2
Baniso -1Baniso -2Baniso -3
1-0.4301 Å20 Å20 Å2
2--0.4301 Å20 Å2
3----0.8602 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: LAST / Resolution: 2.303→41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2216 0 60 133 2409
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082330HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.963160HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d794SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes383HARMONIC5
X-RAY DIFFRACTIONt_it2327HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion284SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact2001SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.03
X-RAY DIFFRACTIONt_other_torsion16.87
LS refinement shellResolution: 2.303→2.35 Å
RfactorNum. reflection% reflection
Rfree0.2914 21 -
Rwork0.2301 --
obs--49.58 %
Refinement TLS params.Origin x: 9.2876 Å / Origin y: -31.3083 Å / Origin z: 14.2645 Å
111213212223313233
T-0.0396 Å20.01 Å20.0917 Å2--0.191 Å20.0808 Å2---0.1292 Å2
L2.8562 °20.4329 °20.3394 °2-2.4124 °20.0574 °2--2.5987 °2
S0.0137 Å °0.4013 Å °0.0777 Å °0.4013 Å °-0.0074 Å °0.072 Å °0.0777 Å °0.072 Å °-0.0063 Å °
Refinement TLS groupSelection details: { A|* }

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