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

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Basic information

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


behavioral response to formalin induced pain / neurotrophin p75 receptor binding / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / programmed cell death involved in cell development / Signalling to STAT3 / neurotrophin receptor activity / mechanoreceptor differentiation ...behavioral response to formalin induced pain / neurotrophin p75 receptor binding / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / programmed cell death involved in cell development / Signalling to STAT3 / neurotrophin receptor activity / mechanoreceptor differentiation / nerve growth factor receptor activity / neurotrophin binding / Sertoli cell development / axonogenesis involved in innervation / GPI-linked ephrin receptor activity / nerve growth factor signaling pathway / Retrograde neurotrophin signalling / nerve growth factor binding / NGF-independant TRKA activation / sympathetic nervous system development / Signalling to p38 via RIT and RIN / ARMS-mediated activation / positive regulation of Ras protein signal transduction / positive regulation of programmed cell death / positive regulation of synapse assembly / PI3K/AKT activation / Frs2-mediated activation / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / detection of temperature stimulus involved in sensory perception of pain / neurotrophin TRK receptor signaling pathway / response to axon injury / neuron development / Signalling to RAS / detection of mechanical stimulus involved in sensory perception of pain / response to electrical stimulus / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / positive regulation of synaptic transmission, glutamatergic / response to nutrient levels / B cell differentiation / cellular response to nerve growth factor stimulus / positive regulation of GTPase activity / axon guidance / receptor protein-tyrosine kinase / kinase binding / positive regulation of neuron projection development / cellular response to nicotine / circadian rhythm / peptidyl-tyrosine phosphorylation / recycling endosome membrane / positive regulation of angiogenesis / neuron projection development / late endosome / late endosome membrane / positive regulation of NF-kappaB transcription factor activity / early endosome membrane / protein tyrosine kinase activity / neuron apoptotic process / negative regulation of neuron apoptotic process / protein autophosphorylation / learning or memory / positive regulation of ERK1 and ERK2 cascade / early endosome / receptor complex / endosome membrane / response to xenobiotic stimulus / positive regulation of protein phosphorylation / negative regulation of cell population proliferation / axon / protein phosphorylation / neuronal cell body / dendrite / negative regulation of apoptotic process / cell surface / protein homodimerization activity / protein-containing complex / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
High affinity nerve growth factor receptor NTRK1 / Tyrosine kinase receptor A, transmembrane domain / Tyrosine kinase receptor A trans-membrane domain / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / 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. ...High affinity nerve growth factor receptor NTRK1 / Tyrosine kinase receptor A, transmembrane domain / Tyrosine kinase receptor A trans-membrane domain / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / 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. / Leucine rich repeat / Leucine-rich repeat / Leucine-rich repeat domain 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 / 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-4EK / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.0229 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 9, 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: High affinity nerve growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1938
Polymers34,2621
Non-polymers9327
Water1,40578
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)105.747, 105.747, 204.684
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

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Components

#1: Protein High affinity nerve growth factor receptor / Neurotrophic tyrosine kinase receptor type 1 / TRK1-transforming tyrosine kinase protein / ...Neurotrophic tyrosine kinase receptor type 1 / TRK1-transforming tyrosine kinase protein / Tropomyosin-related kinase A / Tyrosine kinase receptor / Tyrosine kinase receptor A / Trk-A / gp140trk / p140-TrkA


Mass: 34261.613 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK1, MTC, TRK, TRKA / Plasmid: pFastBac1-HM / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-4EK / 6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]-3-(pyridin-2-yl)imidazo[1,2-b]pyridazine


Mass: 359.400 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18FN5
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 78 / 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: 3.23 Å3/Da / Density % sol: 62 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 0.8M (NH4)2SO4, 0.1M Citrate pH 5.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 28, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2.02→34.13 Å / Num. obs: 29032 / % possible obs: 99.81 % / Redundancy: 5.6 % / Biso Wilson estimate: 45.64 Å2 / Rmerge(I) obs: 0.035 / Net I/σ(I): 12.3
Reflection shellResolution: 2.02→2.05 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.575 / % possible all: 100

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Processing

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

3v5q


Resolution: 2.0229→34.129 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2163 1474 5.08 %Random Selection
Rwork0.1829 ---
obs0.1846 28997 99.69 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.66 Å2
Refinement stepCycle: LAST / Resolution: 2.0229→34.129 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2190 0 58 78 2326
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082314
X-RAY DIFFRACTIONf_angle_d1.0573141
X-RAY DIFFRACTIONf_dihedral_angle_d13.982816
X-RAY DIFFRACTIONf_chiral_restr0.05335
X-RAY DIFFRACTIONf_plane_restr0.005399
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0229-2.08820.28741350.25622475X-RAY DIFFRACTION99
2.0882-2.16280.24811260.23052457X-RAY DIFFRACTION100
2.1628-2.24930.25321430.2152491X-RAY DIFFRACTION100
2.2493-2.35170.23041380.20892477X-RAY DIFFRACTION100
2.3517-2.47570.28331280.19822483X-RAY DIFFRACTION100
2.4757-2.63070.21561490.19312443X-RAY DIFFRACTION100
2.6307-2.83370.26051260.20132519X-RAY DIFFRACTION100
2.8337-3.11870.23791390.19342512X-RAY DIFFRACTION100
3.1187-3.56960.21841480.19012501X-RAY DIFFRACTION100
3.5696-4.49570.16231260.15862548X-RAY DIFFRACTION100
4.4957-34.10.22041160.17342617X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: -25.6387 Å / Origin y: -42.9463 Å / Origin z: -19.4055 Å
111213212223313233
T0.3802 Å20.0466 Å20.0393 Å2-0.292 Å2-0.0233 Å2--0.2725 Å2
L4.2519 °20.7625 °20.8591 °2-1.9296 °20.1315 °2--4.099 °2
S-0.209 Å °-0.0792 Å °0.0846 Å °-0.1791 Å °-0.0313 Å °0.0772 Å °-0.3414 Å °0.1636 Å °0.1902 Å °
Refinement TLS groupSelection details: all

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