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- PDB-7nzn: Structure of RET kinase domain bound to inhibitor JB-48 -

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Basic information

Entry
Database: PDB / ID: 7nzn
TitleStructure of RET kinase domain bound to inhibitor JB-48
ComponentsProto-oncogene tyrosine-protein kinase receptor Ret
KeywordsTRANSFERASE / Kinase / Inhibitor / Cancer / Receptor Tyrosine 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
FORMIC ACID / Chem-VJH / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.39 Å
AuthorsBriggs, D.C. / McDonald, N.Q.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
The Francis Crick Institute United Kingdom
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose.
Authors: Zhang, L. / Moccia, M. / Briggs, D.C. / Bharate, J.B. / Lakkaniga, N.R. / Knowles, P. / Yan, W. / Tran, P. / Kharbanda, A. / Wang, X. / Leung, Y.K. / Frett, B. / Santoro, M. / McDonald, N.Q. ...Authors: Zhang, L. / Moccia, M. / Briggs, D.C. / Bharate, J.B. / Lakkaniga, N.R. / Knowles, P. / Yan, W. / Tran, P. / Kharbanda, A. / Wang, X. / Leung, Y.K. / Frett, B. / Santoro, M. / McDonald, N.Q. / Carlomagno, F. / Li, H.Y.
History
DepositionMar 24, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 9, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)36,5615
Polymers35,8681
Non-polymers6934
Water77543
1
A: Proto-oncogene tyrosine-protein kinase receptor Ret
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)73,12210
Polymers71,7362
Non-polymers1,3858
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,y,-z1
Buried area3940 Å2
ΔGint-20 kcal/mol
Surface area24980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.910, 71.090, 80.180
Angle α, β, γ (deg.)90.000, 101.580, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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


Mass: 35868.191 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Residues 700-705 are vector derived sequence. / Source: (gene. exp.) Homo sapiens (human) / Gene: RET, CDHF12, CDHR16, PTC, RET51 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07949, receptor protein-tyrosine kinase
#2: Chemical ChemComp-VJH / 2-[4-[[4-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]-6-[(3-methyl-1~{H}-pyrazol-5-yl)amino]pyrimidin-2-yl]amino]phenyl]-~{N}-(3-fluorophenyl)ethanamide


Mass: 554.621 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H31FN10O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: CH2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 43 / 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: 2.84 Å3/Da / Density % sol: 56.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 2-3M sodium formate 100mM sodium acetate pH 4.5-6 / PH range: 4.5-6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.39→39.92 Å / Num. obs: 15912 / % possible obs: 99.24 % / Redundancy: 6 % / Biso Wilson estimate: 47.34 Å2 / CC1/2: 0.977 / CC star: 0.994 / Net I/σ(I): 6.63
Reflection shellResolution: 2.39→2.475 Å / Redundancy: 6.1 % / Mean I/σ(I) obs: 2.18 / Num. unique obs: 1556 / CC1/2: 0.454 / CC star: 0.079 / % possible all: 99.3

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4CKJ

4ckj


Resolution: 2.39→39.92 Å / SU ML: 0.3853 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.8308
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2541 799 5.03 %
Rwork0.2128 15098 -
obs0.2148 15897 99.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.47 Å2
Refinement stepCycle: LAST / Resolution: 2.39→39.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2267 0 50 43 2360
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00172369
X-RAY DIFFRACTIONf_angle_d0.44713199
X-RAY DIFFRACTIONf_chiral_restr0.0385343
X-RAY DIFFRACTIONf_plane_restr0.0025400
X-RAY DIFFRACTIONf_dihedral_angle_d15.1777864
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.39-2.540.37961420.3152512X-RAY DIFFRACTION99.33
2.54-2.740.3311350.31742473X-RAY DIFFRACTION99.28
2.74-3.010.31941230.28222525X-RAY DIFFRACTION99.66
3.01-3.450.29721120.22682541X-RAY DIFFRACTION99.62
3.45-4.340.23681390.18322513X-RAY DIFFRACTION99.51
4.34-39.920.19611480.16992534X-RAY DIFFRACTION98.24
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)
10.708560629909-1.0613531926-0.8986057883092.386418167171.702476291722.56286916017-0.1447856750740.316768976506-0.4948070200210.3868020703870.09128714793950.279220301660.392295303668-0.1385245032957.73224554814E-50.4350911999130.0737775544350.02968580425160.3914824630490.01422339891570.67893432421915.44283969545.19819358032.6808831515
21.65212190936-1.12010584406-0.1194398583121.132990456480.0856952428511.17616727636-0.05456193863530.127862045301-0.161286174978-0.1279420980760.03900759844620.103272871027-0.02084717580160.02502006243680.004181977034230.3625090160510.0159982038460.1267301314680.403841288678-0.01985136835910.44629634423120.41649665511.947529623567.05165438975
32.50711759258-1.135799477171.240515395643.97374195634-0.7173525163913.69342189185-0.153346187149-0.3333968257130.06102546097580.3014831045280.2043175445620.0823928001329-0.302734120155-0.1514370679660.02574379364230.2731721678920.1251375124630.08353626871290.403322972944-0.06378666608880.2592377836226.65494248788.0320835793719.4590645501
41.978491597670.07729934361560.598290969482.21310522148-0.6474139219522.263955097180.179374030003-0.2680545149510.594586495541-0.490575762902-0.182568851839-0.0215803122592-0.368576861047-0.2560581554790.02222161908070.3900679806060.1039958382680.04961819444140.437435388804-0.009001550798930.38322506821427.55501793823.2399957091418.4774694935
53.903591843250.0652046679986-0.927670339364.031705640690.9208569617913.84241379208-0.133596083048-0.163671640294-0.3020546870060.1046659676280.05907076355320.01003948102820.1420866792890.148064781497-0.00318980283840.36008585690.06194717551810.02533737510080.3929741122240.05078835067740.3990441726939.7571812771-4.8207502675914.9618472874
62.70055209998-0.736597266726-1.09493887520.718459811519-0.07343997550272.74004261807-0.000686276068108-0.492782278667-0.01992285218930.5899686522120.129767352679-0.1482454985990.3540955668410.104578034732-0.0001244837910380.6161394130350.07176441812740.06842398209440.8231782968510.0638814216810.48685740765740.9535982787-0.95182807923830.9176034932
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 700 through 751 )700 - 7511 - 50
22chain 'A' and (resid 752 through 794 )752 - 79451 - 93
33chain 'A' and (resid 795 through 867 )795 - 86794 - 143
44chain 'A' and (resid 868 through 890 )868 - 890144 - 166
55chain 'A' and (resid 891 through 965 )891 - 965167 - 241
66chain 'A' and (resid 966 through 1013 )966 - 1013242 - 289

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