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- PDB-7dua: Crystal structure of human Proto-oncogene tyrosine-protein kinase... -

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Basic information

Entry
Database: PDB / ID: 7dua
TitleCrystal structure of human Proto-oncogene tyrosine-protein kinase receptor Ret in complex with 4-amino-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide
ComponentsProto-oncogene tyrosine-protein kinase receptor Ret
KeywordsTRANSFERASE / TYROSINE-PROTEIN KINASE
Function / homology
Function and homology information


Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / Formation of the ureteric bud ...Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / Formation of the ureteric bud / positive regulation of neuron maturation / Formation of the nephric duct / enteric nervous system development / neuron cell-cell adhesion / 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 / 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 / early endosome / receptor complex / endosome membrane / positive regulation of cell migration / response to xenobiotic stimulus / axon / protein phosphorylation / neuronal cell body / calcium ion binding / dendrite / 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
Chem-HJ0 / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.64 Å
AuthorsMiyazaki, I. / Ishida, K. / Suzuki, T.
CitationJournal: To be published
Title: Selective RET inhibitor TAS0953/HM06
Authors: Miyazaki, I. / Ishida, K. / Suzuki, T.
History
DepositionJan 8, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)72,0394
Polymers71,4162
Non-polymers6232
Water6,648369
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2680 Å2
ΔGint-18 kcal/mol
Surface area24940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.714, 80.215, 79.677
Angle α, β, γ (deg.)90.000, 99.400, 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 / Fragment: kinase domain
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-HJ0 / 4-azanyl-7-(1-methylcyclopropyl)-~{N}-(5-methyl-1~{H}-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide


Mass: 311.342 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H17N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 369 / 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: 2.37 Å3/Da / Density % sol: 48.11 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion
Details: 0.20 M LiCl, 0.10 M Na Asetate, pH5.00, 3 M Na Formate, 5 mM MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.64→78.63 Å / Num. obs: 75166 / % possible obs: 97.5 % / Redundancy: 4.2 % / Rrim(I) all: 0.057 / Rsym value: 0.05 / Net I/σ(I): 16.67
Reflection shellResolution: 1.64→1.89 Å / Redundancy: 4.3 % / Mean I/σ(I) obs: 3.84 / Num. unique obs: 25733 / Rrim(I) all: 0.491 / Rsym value: 0.431 / % possible all: 96.8

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.64→78.63 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.949 / SU B: 3.012 / SU ML: 0.071 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.099 / ESU R Free: 0.096 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2177 3698 4.9 %RANDOM
Rwork0.1907 ---
obs0.1921 71467 97.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 81.18 Å2 / Biso mean: 26.736 Å2 / Biso min: 11.42 Å2
Baniso -1Baniso -2Baniso -3
1-1.54 Å20 Å20.06 Å2
2---0.29 Å20 Å2
3----1.2 Å2
Refinement stepCycle: final / Resolution: 1.64→78.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4503 0 46 369 4918
Biso mean--17.81 33.66 -
Num. residues----561
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0194661
X-RAY DIFFRACTIONr_bond_other_d0.0030.024548
X-RAY DIFFRACTIONr_angle_refined_deg1.4291.9836308
X-RAY DIFFRACTIONr_angle_other_deg1.202310443
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4585573
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.48623.053190
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.57415833
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6091533
X-RAY DIFFRACTIONr_chiral_restr0.0830.2679
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215203
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021072
LS refinement shellResolution: 1.64→1.683 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.329 243 -
Rwork0.297 5201 -
all-5444 -
obs--96.32 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.4564-0.72491.25680.99980.81041.85750.03190.0989-0.15890.0170.02550.00570.07950.0786-0.05730.0372-0.01270.03430.0705-0.00430.13144.679-7.779-5.856
22.0755-0.0758-0.45211.3439-0.03681.4283-0.0107-0.04370.10010.09210.004-0.0007-0.06380.03290.00670.00940.0003-0.00380.05890.00180.068921.664.6917.645
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A712 - 807
2X-RAY DIFFRACTION2A808 - 1011

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