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- PDB-4ymj: (R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Clas... -

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Basic information

Entry
Database: PDB / ID: 4ymj
Title(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors
ComponentsNT-3 growth factor receptor
KeywordsTransferase/Transferase inhibitor / Kinase / TRK / Inhibitor / Oncology / Transferase-Transferase inhibitor complex
Function / homology
Function and homology information


NTF3 activates NTRK3 signaling / Activated NTRK3 signals through PLCG1 / Signaling by NTRK3 (TRKC) / Receptor-type tyrosine-protein phosphatases / NTRK3 as a dependence receptor / neurotrophin receptor activity / neurotrophin binding / Activated NTRK3 signals through PI3K / activation of GTPase activity / positive regulation of positive chemotaxis ...NTF3 activates NTRK3 signaling / Activated NTRK3 signals through PLCG1 / Signaling by NTRK3 (TRKC) / Receptor-type tyrosine-protein phosphatases / NTRK3 as a dependence receptor / neurotrophin receptor activity / neurotrophin binding / Activated NTRK3 signals through PI3K / activation of GTPase activity / positive regulation of positive chemotaxis / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Activated NTRK3 signals through RAS / cell surface receptor protein tyrosine kinase signaling pathway / activation of protein kinase B activity / transmembrane receptor protein tyrosine kinase activity / cellular response to nerve growth factor stimulus / negative regulation of protein phosphorylation / positive regulation of MAP kinase activity / receptor protein-tyrosine kinase / positive regulation of neuron projection development / p53 binding / positive regulation of peptidyl-serine phosphorylation / nervous system development / heart development / cell differentiation / receptor complex / positive regulation of cell migration / positive regulation of protein phosphorylation / phosphorylation / axon / positive regulation of cell population proliferation / positive regulation of gene expression / ATP binding / plasma membrane
Similarity search - Function
NT-3 growth factor receptor NTRK3 / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Tyrosine-protein kinase, receptor class II, conserved site ...NT-3 growth factor receptor NTRK3 / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Immunoglobulin / Immunoglobulin domain / Leucine rich repeat / Immunoglobulin I-set / Immunoglobulin I-set domain / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-4EJ / NT-3 growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsKreusch, A. / Rucker, P. / Molteni, V. / Loren, J.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.
Authors: Choi, H.S. / Rucker, P.V. / Wang, Z. / Fan, Y. / Albaugh, P. / Chopiuk, G. / Gessier, F. / Sun, F. / Adrian, F. / Liu, G. / Hood, T. / Li, N. / Jia, Y. / Che, J. / McCormack, S. / Li, A. / ...Authors: Choi, H.S. / Rucker, P.V. / Wang, Z. / Fan, Y. / Albaugh, P. / Chopiuk, G. / Gessier, F. / Sun, F. / Adrian, F. / Liu, G. / Hood, T. / Li, N. / Jia, Y. / Che, J. / McCormack, S. / Li, A. / Li, J. / Steffy, A. / Culazzo, A. / Tompkins, C. / Phung, V. / Kreusch, A. / Lu, M. / Hu, B. / Chaudhary, A. / Prashad, M. / Tuntland, T. / Liu, B. / Harris, J. / Seidel, H.M. / Loren, J. / Molteni, V.
History
DepositionMar 6, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 3, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NT-3 growth factor receptor
B: NT-3 growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,69311
Polymers69,4552
Non-polymers1,2399
Water6,900383
1
A: NT-3 growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3646
Polymers34,7271
Non-polymers6375
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: NT-3 growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3295
Polymers34,7271
Non-polymers6024
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.610, 65.610, 175.622
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number145
Space group name H-MP32

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Components

#1: Protein NT-3 growth factor receptor / GP145-TrkC / Trk-C / Neurotrophic tyrosine kinase receptor type 3 / TrkC tyrosine kinase


Mass: 34727.312 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Sequence refers to NTRK3 isoform b precursor (NP_002521.2)
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK3, TRKC / Plasmid: [FastBact-HM / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q16288, receptor protein-tyrosine kinase
#2: Chemical ChemComp-4EJ / 4-[6-(benzylamino)imidazo[1,2-b]pyridazin-3-yl]benzonitrile


Mass: 325.367 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H15N5
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 383 / Source method: isolated from a natural source / Formula: H2O

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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: 3.14 Å3/Da / Density % sol: 60.85 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 6.2 / Details: 2.5 M NACL, 0.1 M NA/K PHOSPHATE PH 6.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 7, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.92→50 Å / Num. obs: 49818 / % possible obs: 87.19 % / Redundancy: 3.2 % / Biso Wilson estimate: 32 Å2 / Rmerge(I) obs: 0.079 / Net I/σ(I): 14
Reflection shellResolution: 1.92→1.96 Å / Rmerge(I) obs: 0.73 / % possible all: 78.1

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1692)refinement
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3V5Q

3v5q


Resolution: 2→47.704 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 20.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1993 2479 4.98 %Random
Rwork0.1646 ---
obs0.1664 49818 87.19 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2→47.704 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4352 0 87 383 4822
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084570
X-RAY DIFFRACTIONf_angle_d1.0246177
X-RAY DIFFRACTIONf_dihedral_angle_d15.5771710
X-RAY DIFFRACTIONf_chiral_restr0.045666
X-RAY DIFFRACTIONf_plane_restr0.005828
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0001-2.03860.25891280.22372369X-RAY DIFFRACTION78
2.0386-2.08020.22051270.19642512X-RAY DIFFRACTION84
2.0802-2.12540.25931290.1972692X-RAY DIFFRACTION88
2.1254-2.17490.26481420.19522567X-RAY DIFFRACTION85
2.1749-2.22930.23181470.18652620X-RAY DIFFRACTION88
2.2293-2.28950.22391430.18222668X-RAY DIFFRACTION89
2.2895-2.35690.2181360.17212542X-RAY DIFFRACTION83
2.3569-2.4330.20361140.16772725X-RAY DIFFRACTION89
2.433-2.51990.221220.17472667X-RAY DIFFRACTION87
2.5199-2.62080.20041350.17682632X-RAY DIFFRACTION89
2.6208-2.74010.19541230.17282691X-RAY DIFFRACTION88
2.7401-2.88450.22671720.16862692X-RAY DIFFRACTION90
2.8845-3.06520.1971540.17022623X-RAY DIFFRACTION88
3.0652-3.30180.22391460.16552702X-RAY DIFFRACTION90
3.3018-3.6340.18051550.14242693X-RAY DIFFRACTION90
3.634-4.15960.16751340.14482678X-RAY DIFFRACTION89
4.1596-5.23960.17421240.13622687X-RAY DIFFRACTION89
5.2396-47.71760.18871480.18592579X-RAY DIFFRACTION86
Refinement TLS params.Method: refined / Origin x: -5.538 Å / Origin y: -9.0101 Å / Origin z: 11.0436 Å
111213212223313233
T0.284 Å2-0.0015 Å2-0.0208 Å2-0.187 Å2-0.0228 Å2--0.2071 Å2
L1.2424 °2-0.1548 °20.248 °2-0.0957 °2-0.0399 °2--0.2432 °2
S-0.018 Å °-0.0214 Å °-0.03 Å °0.01 Å °-0.0123 Å °-0.0068 Å °0.0373 Å °-0.0016 Å °0.0162 Å °
Refinement TLS groupSelection details: all

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