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Yorodumi- PDB-4yps: (R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Clas... -
+Open data
-Basic information
Entry | Database: PDB / ID: 4yps | ||||||
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Title | (R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors | ||||||
Components | High affinity nerve growth factor receptor | ||||||
Keywords | Transfease/Transferase Inhibitor / TrkA / Kinase / Oncology / Inhibitor complex. / Transfease-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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1012 Å | ||||||
Authors | Kreusch, A. / Rucker, P. / Molteni, V. / Loren, J. | ||||||
Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4yps.cif.gz | 132.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4yps.ent.gz | 101.6 KB | Display | PDB format |
PDBx/mmJSON format | 4yps.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 4yps_validation.pdf.gz | 881.9 KB | Display | wwPDB validaton report |
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Full document | 4yps_full_validation.pdf.gz | 884.3 KB | Display | |
Data in XML | 4yps_validation.xml.gz | 12.8 KB | Display | |
Data in CIF | 4yps_validation.cif.gz | 17 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/yp/4yps ftp://data.pdbj.org/pub/pdb/validation_reports/yp/4yps | HTTPS FTP |
-Related structure data
Related structure data | 4ymjC 4yneSC S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | 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 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) References: UniProt: P04629, receptor protein-tyrosine kinase | ||
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#2: Chemical | ChemComp-4F6 / | ||
#3: Chemical | ChemComp-SO4 / #4: Water | ChemComp-HOH / | |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 3.26 Å3/Da / Density % sol: 62.23 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 0.8M (NH4)2SO4, 0.1M Citrate pH 5.0 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 29, 2012 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9765 Å / Relative weight: 1 |
Reflection | Resolution: 2.1→34.36 Å / Num. obs: 26115 / % possible obs: 99.7 % / Redundancy: 5.4 % / Biso Wilson estimate: 48 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 7.8 |
Reflection shell | Resolution: 2.1→2.14 Å / % possible all: 94.7 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4YNE Resolution: 2.1012→34.36 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 0.27 / Phase error: 29.64 / Stereochemistry target values: ML
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 67 Å2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.1012→34.36 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Origin x: -25.9658 Å / Origin y: -43.7469 Å / Origin z: -19.6069 Å
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Refinement TLS group | Selection details: all |