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- PDB-7du9: Crystal structure of human Proto-oncogene tyrosine-protein kinase... -

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Basic information

Entry
Database: PDB / ID: 7du9
TitleCrystal structure of human Proto-oncogene tyrosine-protein kinase receptor Ret in complex with Pralsetinib
ComponentsProto-oncogene tyrosine-protein kinase receptor Ret
KeywordsTRANSFERASE / TYROSINE-PROTEIN KINASE
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
Pralsetinib / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.31 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

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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)72,4844
Polymers71,4162
Non-polymers1,0672
Water3,099172
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3050 Å2
ΔGint-20 kcal/mol
Surface area24470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.887, 80.577, 79.866
Angle α, β, γ (deg.)90.000, 99.720, 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-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 / Pralsetinib


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


Mass: 18.015 Da / Num. of mol.: 172 / 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 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion
Details: 0.20 M LiCl, 0.10 M Na Acetate, pH 4.50, 2.5 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: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 27, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.31→78.72 Å / Num. obs: 27199 / % possible obs: 97.1 % / Redundancy: 2.7 % / Rrim(I) all: 0.119 / Rsym value: 0.094 / Net I/σ(I): 10.45
Reflection shellResolution: 2.31→2.56 Å / Redundancy: 2.7 % / Num. unique obs: 7200 / Rrim(I) all: 0.551 / Rsym value: 0.44 / % possible all: 97.7

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.31→78.72 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.919 / SU B: 19.659 / SU ML: 0.231 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.417 / ESU R Free: 0.25 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.249 1185 4.4 %RANDOM
Rwork0.219 ---
obs0.2204 26013 97.15 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 90.76 Å2 / Biso mean: 39.012 Å2 / Biso min: 18.29 Å2
Baniso -1Baniso -2Baniso -3
1-1.54 Å2-0 Å20.15 Å2
2---0.47 Å20 Å2
3----1.06 Å2
Refinement stepCycle: final / Resolution: 2.31→78.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4478 0 86 172 4736
Biso mean--29.1 36.32 -
Num. residues----558
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194627
X-RAY DIFFRACTIONr_bond_other_d0.0030.024495
X-RAY DIFFRACTIONr_angle_refined_deg1.5511.9936250
X-RAY DIFFRACTIONr_angle_other_deg1.229310328
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3155552
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.63523.2200
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.10215.107838
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.1561532
X-RAY DIFFRACTIONr_chiral_restr0.0820.2670
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215103
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021056
LS refinement shellResolution: 2.31→2.37 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.297 85 -
Rwork0.306 1927 -
all-2012 -
obs--98.63 %
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)
13.959-0.94970.5210.29370.12521.82040.06190.1126-0.4164-0.0552-0.00740.05060.1532-0.0128-0.05460.1635-0.02680.06640.3015-0.04280.15464.715-7.398-6.246
23.02950.1726-0.47882.08470.33962.2188-0.0025-0.0880.15780.19740.01470.0654-0.0540.006-0.01230.0829-0.00560.02780.27040.00620.01921.6334.8077.814
30.0491-0.32940.16122.8297-1.52890.91570.0293-0.03160.0054-0.1416-0.1007-0.1314-0.05250.10580.07140.2280.00470.03220.4046-0.04570.083533.5215.403-20.402
41.71750.79490.02874.07470.13872.4849-0.0334-0.01870.0528-0.2641-0.08820.29360.0337-0.1880.12160.21380.02510.02960.3131-0.05430.057121.28-2.681-34.708
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A714 - 807
2X-RAY DIFFRACTION2A808 - 1011
3X-RAY DIFFRACTION3B700 - 807
4X-RAY DIFFRACTION4B808 - 1012

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