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- PDB-6nss: TRK-A IN COMPLEX WITH LIGAND 6 -

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Basic information

Entry
Database: PDB / ID: 6nss
TitleTRK-A IN COMPLEX WITH LIGAND 6
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / TRK-A KINASE DOMAIN / HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR / Inhibitor / TRANSFERASE / 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 / 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-L0M / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.97 Å
AuthorsSubramanian, G. / Brown, D.G.
CitationJournal: Acs Chem.Biol. / Year: 2019
Title: Deciphering the Allosteric Binding Mechanism of the Human Tropomyosin Receptor Kinase A ( hTrkA) Inhibitors.
Authors: Subramanian, G. / Johnson, P.D. / Zachary, T. / Roush, N. / Zhu, Y. / Bowen, S.J. / Janssen, A. / Duclos, B.A. / Williams, T. / Javens, C. / Shalaly, N.D. / Molina, D.M. / Wittwer, A.J. / Hirsch, J.L.
History
DepositionJan 25, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Mar 13, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
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)35,7962
Polymers35,3491
Non-polymers4471
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.075, 52.075, 227.072
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number151
Space group name H-MP3112

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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: 35348.746 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
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)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-L0M / N-(8-methyl-2-phenylimidazo[1,2-a]pyrazin-3-yl)-2-(10H-phenoxazin-10-yl)acetamide


Mass: 447.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H21N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 131 / 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: 2.54 Å3/Da / Density % sol: 51.61 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.10M KH2PO4/ 0.10M NaH2PO4/ 0.1M MES/NaOH pH = 6.00 and 1.9M NaCl (cryo: 25% glycerol in reservoir), or 18% (w/v) PEG 3350, 0.2M CaCl2, 0.10M, MES pH = 6.50 (cryo: direct).

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.97→75.69 Å / Num. obs: 25374 / % possible obs: 99.4 % / Observed criterion σ(I): 0 / Redundancy: 4.2 % / Rmerge(I) obs: 0.054 / Net I/σ(I): 18.74
Reflection shellResolution: 1.97→2.22 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.427 / Num. unique obs: 25374 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
XSCALEdata scaling
Coot0.8.2model building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.97→45.14 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.94 / SU B: 7.653 / SU ML: 0.107 / Cross valid method: THROUGHOUT / ESU R: 0.159 / ESU R Free: 0.145 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21805 1980 7.8 %RANDOM
Rwork0.18063 ---
obs0.18362 23394 99.39 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.164 Å2
Baniso -1Baniso -2Baniso -3
1-0.31 Å20.15 Å2-0 Å2
2--0.31 Å20 Å2
3----1 Å2
Refinement stepCycle: 1 / Resolution: 1.97→45.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2423 0 34 131 2588
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0132451
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172262
X-RAY DIFFRACTIONr_angle_refined_deg1.881.6353332
X-RAY DIFFRACTIONr_angle_other_deg1.4871.5685197
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7315302
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.89721.148122
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.94215377
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0681517
X-RAY DIFFRACTIONr_chiral_restr0.0960.2302
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.022772
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02547
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_it2.4813.0021214
X-RAY DIFFRACTIONr_mcbond_other2.4683.0011213
X-RAY DIFFRACTIONr_mcangle_it3.6934.4811514
X-RAY DIFFRACTIONr_mcangle_other3.6924.4811515
X-RAY DIFFRACTIONr_scbond_it3.2343.2491237
X-RAY DIFFRACTIONr_scbond_other3.2333.2491237
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.8144.7531819
X-RAY DIFFRACTIONr_long_range_B_refined6.43734.4192757
X-RAY DIFFRACTIONr_long_range_B_other6.3834.2452736
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.97→2.021 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.273 141 -
Rwork0.255 1639 -
obs--94.93 %
Refinement TLS params.Method: refined / Origin x: -15.2755 Å / Origin y: 5.4334 Å / Origin z: -17.9552 Å
111213212223313233
T0.034 Å2-0.0244 Å20.0029 Å2-0.0272 Å2-0.0109 Å2--0.011 Å2
L0.4059 °20.2414 °2-0.2702 °2-0.3506 °20.0584 °2--0.5122 °2
S0.0131 Å °0.0148 Å °-0.0483 Å °0.0816 Å °-0.0309 Å °-0.0267 Å °0.0388 Å °-0.0081 Å °0.0178 Å °

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