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- PDB-6npt: TRK-A IN COMPLEX WITH LIGAND 1 -

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Basic information

Entry
Database: PDB / ID: 6npt
TitleTRK-A IN COMPLEX WITH LIGAND 1
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE / TRK-A KINASE DOMAIN HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR 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 / response to axon injury / 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 / 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-KWY / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.19 Å
AuthorsSubramanian, 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 18, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: High affinity nerve growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2182
Polymers34,8221
Non-polymers3951
Water1,31573
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.084, 52.084, 225.611
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: 34822.027 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-KWY / 4-tert-butyl-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide


Mass: 395.496 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25N3O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / 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: 2.57 Å3/Da / Density % sol: 52.25 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: The protein at a concentration of 10 mg/ml was mixed with 2mM of the ligand (diluted from 100 mM DMSO stock solution) for 1 hour on ice and crystallized at 4 deg C (hanging drop) from: 0.10 ...Details: The protein at a concentration of 10 mg/ml was mixed with 2mM of the ligand (diluted from 100 mM DMSO stock solution) for 1 hour on ice and crystallized at 4 deg C (hanging drop) from: 0.10 M KH2PO4/ 0.10 M NaH2PO4/ 0.10 M MES/NaOH pH 6.00 and 1.90 M NaCl (cryo: 25% glycerol in reservoir), or 18.00 % (w/v) PEG 3350, 0.20 M CaCl2, 0.10 M, 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: Dec 14, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.19→75.2 Å / Num. obs: 18386 / % possible obs: 99.1 % / Observed criterion σ(I): 0 / Redundancy: 4.1 % / Rmerge(I) obs: 0.038 / Net I/σ(I): 21.78
Reflection shellResolution: 2.19→2.44 Å / Redundancy: 4 % / Rmerge(I) obs: 0.434 / Num. unique obs: 5012 / % possible all: 99.1

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0049refinement
Coot0.8.2model building
RefinementResolution: 2.19→45.2 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.925 / SU B: 7.105 / SU ML: 0.179 / Cross valid method: THROUGHOUT / ESU R: 0.283 / ESU R Free: 0.233 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27646 1437 7.8 %RANDOM
Rwork0.22334 ---
obs0.22743 16947 99.15 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 52.878 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å20.08 Å2-0 Å2
2--0.15 Å2-0 Å2
3----0.5 Å2
Refinement stepCycle: LAST / Resolution: 2.19→45.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2319 0 30 73 2422
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192348
X-RAY DIFFRACTIONr_bond_other_d0.0010.022241
X-RAY DIFFRACTIONr_angle_refined_deg1.3181.973188
X-RAY DIFFRACTIONr_angle_other_deg2.54435109
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.285284
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.02322.913103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.51715372
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.0341517
X-RAY DIFFRACTIONr_chiral_restr0.0760.2343
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212641
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02573
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_it8.2826.7031148
X-RAY DIFFRACTIONr_mcbond_other8.2716.7021147
X-RAY DIFFRACTIONr_mcangle_it10.44311.2831428
X-RAY DIFFRACTIONr_mcangle_other10.44211.2851429
X-RAY DIFFRACTIONr_scbond_it9.5837.5031198
X-RAY DIFFRACTIONr_scbond_other9.5797.5061199
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other12.42212.2681760
X-RAY DIFFRACTIONr_long_range_B_refined14.18929.9662631
X-RAY DIFFRACTIONr_long_range_B_other14.22129.9752613
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.19→2.247 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 102 -
Rwork0.314 1205 -
obs--97.39 %

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