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- PDB-6j5l: Crystal structure of Trk-A in complex with the Pan-Trk Kinase Inh... -

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Basic information

Entry
Database: PDB / ID: 6j5l
TitleCrystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 10e
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE / Transferase inhibitor
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 / Signalling to STAT3 / programmed cell death involved in cell development / mechanoreceptor differentiation / neurotrophin receptor activity ...behavioral response to formalin induced pain / neurotrophin p75 receptor binding / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / programmed cell death involved in cell development / mechanoreceptor differentiation / neurotrophin receptor activity / nerve growth factor receptor activity / neurotrophin binding / Sertoli cell development / GPI-linked ephrin receptor activity / nerve growth factor signaling pathway / axonogenesis involved in innervation / 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 / detection of temperature stimulus involved in sensory perception of pain / neurotrophin TRK receptor signaling pathway / neuron development / Signalling to RAS / response to axon injury / detection of mechanical stimulus involved in sensory perception of pain / response to electrical stimulus / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / B cell differentiation / positive regulation of synaptic transmission, glutamatergic / positive regulation of GTPase activity / response to nutrient levels / cellular response to nerve growth factor stimulus / axon guidance / receptor protein-tyrosine kinase / kinase binding / positive regulation of neuron projection development / peptidyl-tyrosine phosphorylation / cellular response to nicotine / circadian rhythm / 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 / positive regulation of ERK1 and ERK2 cascade / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / learning or memory / receptor complex / endosome membrane / response to xenobiotic stimulus / positive regulation of protein phosphorylation / protein phosphorylation / negative regulation of cell population proliferation / axon / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-B9C / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsKensuke, A. / Kazutaka, I.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: The discovery of novel 3-aryl-indazole derivatives as peripherally restricted pan-Trk inhibitors for the treatment of pain.
Authors: Shirahashi, H. / Toriihara, E. / Suenaga, Y. / Yoshida, H. / Akaogi, K. / Endou, Y. / Wakabayashi, M. / Takashima, M.
History
DepositionJan 11, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 17, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID
Revision 1.2Aug 28, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)34,7392
Polymers34,2621
Non-polymers4781
Water57632
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.193, 104.193, 203.838
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 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): sf9
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-B9C / N-{2-[({3-[6-(piperazin-1-yl)pyridin-3-yl]-1H-indazol-5-yl}amino)methyl]phenyl}methanesulfonamide


Mass: 477.582 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27N7O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 3.11 Å3/Da / Density % sol: 60.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.3
Details: 0.65 M Ammonium sulfate, 0.1 M Sodium Citrate pH 5.3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NE3A / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Feb 25, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→44.37 Å / Num. obs: 19224 / % possible obs: 99.9 % / Redundancy: 9.6 % / Biso Wilson estimate: 64.854 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.043 / Rpim(I) all: 0.021 / Rrim(I) all: 0.048 / Χ2: 1.04 / Net I/σ(I): 26.2
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 8.8 % / Rmerge(I) obs: 1.434 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1852 / CC1/2: 0.862 / Rpim(I) all: 0.749 / Rrim(I) all: 1.624 / Χ2: 0.99 / % possible all: 99.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSOct 15, 2015data reduction
Aimless0.7.3data scaling
MOLREP11.6.04phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4AOJ

4aoj


Resolution: 2.3→44.09 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.943 / SU B: 8.603 / SU ML: 0.195 / Cross valid method: THROUGHOUT / ESU R: 0.254 / ESU R Free: 0.205 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25078 976 5.1 %RANDOM
Rwork0.22312 ---
obs0.22448 18248 99.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 69.112 Å2
Baniso -1Baniso -2Baniso -3
1-2.19 Å21.09 Å20 Å2
2--2.19 Å20 Å2
3----7.09 Å2
Refinement stepCycle: 1 / Resolution: 2.3→44.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2076 0 34 32 2142
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0132254
X-RAY DIFFRACTIONr_bond_other_d0.0040.0181969
X-RAY DIFFRACTIONr_angle_refined_deg1.6661.7053075
X-RAY DIFFRACTIONr_angle_other_deg1.6271.6444512
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5395280
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.53321.19692
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.67415297
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0321514
X-RAY DIFFRACTIONr_chiral_restr0.0670.2284
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022566
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02513
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it8.1617.751129
X-RAY DIFFRACTIONr_mcbond_other8.1377.7481128
X-RAY DIFFRACTIONr_mcangle_it11.05411.6111406
X-RAY DIFFRACTIONr_mcangle_other11.05211.6151407
X-RAY DIFFRACTIONr_scbond_it8.7587.831125
X-RAY DIFFRACTIONr_scbond_other8.7547.8291126
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other11.96911.5361670
X-RAY DIFFRACTIONr_long_range_B_refined15.6779051
X-RAY DIFFRACTIONr_long_range_B_other15.6819045
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.465 65 -
Rwork0.387 1321 -
obs--98.86 %

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