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- PDB-7run: Crystal structure of phosphorylated RET tyrosine kinase domain co... -

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Basic information

Entry
Database: PDB / ID: 7run
TitleCrystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrrolo[2,3-d]pyrimidine inhibitor.
ComponentsProto-oncogene tyrosine-protein kinase receptor Ret
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / tyrosine-protein kinase / inhibitor / cell adhesion / TRANSFERASE-TRANSFERASE INHIBITOR complex
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-7QU / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.51 Å
AuthorsLee, C.C. / Spraggon, G.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3- d ]pyrimidine RET Inhibitors.
Authors: Mathison, C.J.N. / Yang, Y. / Nelson, J. / Huang, Z. / Jiang, J. / Chianelli, D. / Rucker, P.V. / Roland, J. / Xie, Y.F. / Epple, R. / Bursulaya, B. / Lee, C. / Gao, M.Y. / Shaffer, J. / ...Authors: Mathison, C.J.N. / Yang, Y. / Nelson, J. / Huang, Z. / Jiang, J. / Chianelli, D. / Rucker, P.V. / Roland, 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
DepositionAug 17, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 19, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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)78,2776
Polymers77,3262
Non-polymers9514
Water00
1
A: Proto-oncogene tyrosine-protein kinase receptor Ret
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,1383
Polymers38,6631
Non-polymers4752
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Proto-oncogene tyrosine-protein kinase receptor Ret
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,1383
Polymers38,6631
Non-polymers4752
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)98.131, 98.131, 145.381
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63
Space group name HallP6c
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/2
#3: y,-x+y,z+1/2
#4: -y,x-y,z
#5: -x+y,-x,z
#6: -x,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 706 through 743 or (resid 744...
d_2ens_1(chain "B" and (resid 706 through 746 or (resid 747...
d_1ens_2chain "L"
d_2ens_2chain "M"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1VALARGA2 - 287
d_21ens_1VALVALB1 - 117
d_22ens_1ARGARGB120 - 288
d_11ens_2LI1LI1E
d_21ens_2LI1LI1F

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.999990515882, 0.00376522335237, -0.00218888980608), (0.00376334339979, -0.999992546775, -0.00086234652247), (-0.00219212041906, 0.00085410079987, -0.999997232556)-0.25544476947, 170.038122725, 7.30756932715
2given(0.997085797673, -0.068080367875, -0.0344234743847), (-0.0691646797805, -0.997112392412, -0.0313548077552), (-0.0321894260522, 0.0336443220843, -0.998915362001)6.13730668849, 168.016606154, 3.3402342037

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Components

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


Mass: 38662.883 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 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P07949, receptor protein-tyrosine kinase
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-7QU / 1-(4-{(1s,3s)-3-[4-amino-5-(3-amino-4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutyl}piperazin-1-yl)ethan-1-one


Mass: 439.941 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26ClN7O / Feature type: SUBJECT OF INVESTIGATION
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: 2.61 Å3/Da / Density % sol: 52.93 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 4.6 / Details: 1.8M Ammonium sulfate, 0.1M sodium acetate pH 4.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97648 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 16, 2014
RadiationMonochromator: Single crystal, cylindrically bent, Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97648 Å / Relative weight: 1
ReflectionResolution: 3.5→50 Å / Num. obs: 10093 / % possible obs: 100 % / Redundancy: 5.7 % / Biso Wilson estimate: 59.68 Å2 / CC1/2: 0.996 / CC star: 0.999 / Rpim(I) all: 0.051 / Rrim(I) all: 0.166 / Rsym value: 0.127 / Χ2: 1.062 / Net I/σ(I): 13.1
Reflection shellResolution: 3.5→3.63 Å / Redundancy: 5.7 % / Mean I/σ(I) obs: 1.76 / Num. unique obs: 983 / CC1/2: 0.576 / CC star: 0.855 / Rpim(I) all: 0.494 / Χ2: 0.94 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
HKL-2000data reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6VHG

6vhg


Resolution: 3.51→49.07 Å / SU ML: 0.4677 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 27.8639
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2469 475 5.29 %
Rwork0.2202 8510 -
obs0.2219 8985 89.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.98 Å2
Refinement stepCycle: LAST / Resolution: 3.51→49.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4545 0 64 0 4609
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00224716
X-RAY DIFFRACTIONf_angle_d0.64916398
X-RAY DIFFRACTIONf_chiral_restr0.044690
X-RAY DIFFRACTIONf_plane_restr0.0037850
X-RAY DIFFRACTIONf_dihedral_angle_d16.18921777
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AX-RAY DIFFRACTIONTorsion NCS0.613484016783
ens_2d_2BX-RAY DIFFRACTIONTorsion NCS1.19940298501
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.51-4.010.31791130.2692194X-RAY DIFFRACTION69.91
4.01-5.060.24671810.19343135X-RAY DIFFRACTION100
5.06-49.070.21511810.22083181X-RAY DIFFRACTION99.79
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)
14.2011411007-0.7333542240710.5101379359261.887444790151.252341014622.187637745960.3921386752380.461638708723-0.17783683928-0.259916999475-0.00891074780834-0.5480782828740.2650719539920.796576573651-0.3360963985210.4456889983410.5732465620910.1942942540980.3508625120010.135059178090.785798856588-13.832004960561.37586822321.10765941035
21.898022873680.171255877486-0.007444182534641.52327501617-0.07994295111371.032188357860.0897890430883-0.16614601849-0.1748683158720.0239930277675-0.0536944733369-0.02330074075880.3007679177190.013219665764-0.03255777211420.1300699708850.4391575662250.08331481437220.1340758619170.417396321260.771565025221-25.349099845267.36418348515.12698477064
30.585700236005-0.0848580320533-0.1766733802022.13597038311-1.553098336982.3245887824-0.0166878112914-0.150815230553-0.07191695149740.1790526279680.0394832685071-0.3467419824970.1299741387420.1813844532430.09827675306440.3280692854820.5245808659160.07433691601490.6626607081040.2700292889650.721686242114-10.828916180171.25646234017.00965549228
41.13350198026-0.3615180169380.4474127608082.400950839350.3389850976611.414237399240.0175838359829-0.323598133016-0.04292535139260.5834992974620.241086930774-0.067532723930.2926020486710.2661698744330.004091185902150.2781935808830.3375720240850.1677221332970.6160256082730.268053231760.613890290483-19.492104114673.375637474118.7149107347
51.944862679941.021098701870.8846478247634.387837473580.9797649495415.33775176235-0.22485935679-0.0735774253941-0.07992151136260.1990684991830.357647564019-0.528966383713-0.3557608138911.20117764829-0.03224370810570.2934122843430.189699779266-0.09213969437940.6650178584260.1539357329020.490516183977-12.489519445387.904754477319.9779491881
63.311747839321.77654597198-0.09465860398037.227318986730.8590293057147.90650944329-0.210410956466-0.3862652552710.6765895445740.5453941613540.1638989605960.406817101398-1.225612559710.663317860568-0.1126526084370.739425761880.0628640408751-0.1339289548580.690789871081-0.1661838821490.574310389644-15.833087574797.343682055826.6684260993
72.615890305930.5538568977821.423213118734.481081557811.459386865513.724129462750.119451244052-1.03895937729-0.3230279675231.457002538720.0934847828203-0.4474707301280.1427105739360.4962184513590.0142541875580.9020214379320.0966802843627-0.1952112885660.8808283020630.1606579101420.407167983333-15.884862280683.149305735.534799991
80.8764640005241.15716018782-0.07531927044542.387412238010.8313673540981.236670207590.102784748012-0.2940102976490.0573415879340.0318636552490.0771321642218-0.444003220558-0.3756643324150.713174018582-0.1911469478150.191560456784-0.492968290548-0.1234460965680.3487739007680.3088252889671.19508002887-17.5621290996104.8096907634.99534952733
91.223314708821.50941312245-0.8541611832932.38085467334-1.124473780622.73465238331-0.1321164896960.1633341403220.4450907937460.164549733479-0.05730660597390.0640952238151-0.4348162435080.0923904415178-0.05453448001130.27256307523-0.238366142212-0.0505825922840.3311982064210.1452965542830.698652694924-24.9291139462105.486326311.82006783672
100.3447701399430.507428807796-0.2540080033681.96565152204-1.052375891351.27220964985-0.04258221563050.196200056981-0.0107577160123-0.1297089173240.068541551502-0.505249749497-0.06776670513370.1871991760110.2055752564490.188238192048-0.560309478342-0.1251771866060.6547390638120.3733075539180.829061578903-10.818101046798.69632203050.301698438961
110.755633862373-0.55711425806-1.168724753521.135137385340.4336292079292.15733511117-0.0124836619540.316609693017-0.0499888791007-0.22646597230.1011748668990.332334736885-0.157875850674-0.05602156159840.06326841031840.199573826024-0.349529402826-0.219128703650.4324173204370.3277553423240.854519031582-25.745373602198.1794309325-8.14405378041
122.3819428450.0771686702337-0.1179620940264.38987562355-0.2056857999842.33956810311-0.2911357975380.3510047886630.501745071805-0.7708509524740.228425677164-0.356616023344-0.3038456041950.660277563266-0.02846352794930.322695405948-0.2598598520850.002870208069270.7171000017740.1617904664170.561836503343-14.873108607395.1572085818-13.9031651888
133.29697147621-1.29129481158-0.8320482716794.96197175610.6790025914514.6508608675-0.1821372510460.598226384253-0.407721374577-0.9232460456220.0933520752152-0.3879230466990.4700321744460.7080387004190.2067188027580.452833997794-0.1638967524510.1790464071230.6715625033310.09592677050290.480494848353-14.063840314281.8359784857-19.0870638919
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 705 through 726 )AA705 - 7261 - 22
22chain 'A' and (resid 727 through 765 )AA727 - 76523 - 61
33chain 'A' and (resid 766 through 781 )AA766 - 78162 - 77
44chain 'A' and (resid 782 through 906 )AA782 - 90678 - 181
55chain 'A' and (resid 907 through 956 )AA907 - 956182 - 231
66chain 'A' and (resid 957 through 977 )AA957 - 977232 - 252
77chain 'A' and (resid 978 through 1012 )AA978 - 1012253 - 287
88chain 'B' and (resid 706 through 736 )BB706 - 7361 - 31
99chain 'B' and (resid 737 through 765 )BB737 - 76532 - 60
1010chain 'B' and (resid 766 through 781 )BB766 - 78161 - 76
1111chain 'B' and (resid 782 through 847 )BB782 - 84777 - 123
1212chain 'B' and (resid 848 through 906 )BB848 - 906124 - 182
1313chain 'B' and (resid 907 through 1012 )BB907 - 1012183 - 288

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