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- PDB-4pmp: The structure of TrkA kinase bound to the inhibitor 1-cyclopropyl... -

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Basic information

Entry
Database: PDB / ID: 4pmp
TitleThe structure of TrkA kinase bound to the inhibitor 1-cyclopropyl-1-[3-(1,3-thiazol-2-yl)benzyl]-3-[4-(trifluoromethoxy)phenyl]urea
ComponentsHigh affinity nerve growth factor receptor
KeywordsTransferase/Transferase inhibitor / kinase / 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-31W / ACETATE ION / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.8 Å
AuthorsSu, H.P.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.
Authors: Stachel, S.J. / Sanders, J.M. / Henze, D.A. / Rudd, M.T. / Su, H.P. / Li, Y. / Nanda, K.K. / Egbertson, M.S. / Manley, P.J. / Jones, K.L. / Brnardic, E.J. / Green, A. / Grobler, J.A. / ...Authors: Stachel, S.J. / Sanders, J.M. / Henze, D.A. / Rudd, M.T. / Su, H.P. / Li, Y. / Nanda, K.K. / Egbertson, M.S. / Manley, P.J. / Jones, K.L. / Brnardic, E.J. / Green, A. / Grobler, J.A. / Hanney, B. / Leitl, M. / Lai, M.T. / Munshi, V. / Murphy, D. / Rickert, K. / Riley, D. / Krasowska-Zoladek, A. / Daley, C. / Zuck, P. / Kane, S.A. / Bilodeau, M.T.
History
DepositionMay 22, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 18, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 1, 2014Group: Database references
Revision 1.2Feb 25, 2015Group: Derived calculations
Revision 1.3Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / diffrn_radiation_wavelength / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_oper_list / pdbx_struct_special_symmetry / refine_hist
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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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)33,8786
Polymers33,2321
Non-polymers6465
Water3,081171
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.543, 75.543, 112.508
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Components on special symmetry positions
IDModelComponents
11A-802-

CL

21A-903-

HOH

31A-957-

HOH

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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: 33232.367 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 501-787)
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-31W / 1-cyclopropyl-1-[3-(1,3-thiazol-2-yl)benzyl]-3-[4-(trifluoromethoxy)phenyl]urea


Mass: 433.447 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18F3N3O2S
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / 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: 2.79 Å3/Da / Density % sol: 55.89 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1M Bis-Tris, 2.3M AmmoniumAcetate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Apr 9, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→65.42 Å / Num. obs: 32854 / % possible obs: 97.7 % / Redundancy: 5.3 % / Biso Wilson estimate: 21.81 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.029 / Net I/σ(I): 18.5 / Num. measured all: 174135
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
1.8-1.973.90.2934.42823172900.9240.16191.6
4.41-65.425.60.03642.81290022840.9980.01698.2

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Processing

Software
NameVersionClassification
XDSdata reduction
PDB_EXTRACT3.14data extraction
BUSTER2.11.5refinement
RefinementResolution: 1.8→23.86 Å / Cor.coef. Fo:Fc: 0.9469 / Cor.coef. Fo:Fc free: 0.9322 / SU R Cruickshank DPI: 0.098 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.098 / SU Rfree Blow DPI: 0.091 / SU Rfree Cruickshank DPI: 0.092
RfactorNum. reflection% reflectionSelection details
Rfree0.1851 1641 5 %RANDOM
Rwork0.1652 ---
obs0.1662 32834 97.55 %-
Displacement parametersBiso max: 119.1 Å2 / Biso mean: 29.89 Å2 / Biso min: 9.83 Å2
Baniso -1Baniso -2Baniso -3
1--2.9716 Å20 Å20 Å2
2---2.9716 Å20 Å2
3---5.9431 Å2
Refine analyzeLuzzati coordinate error obs: 0.164 Å
Refinement stepCycle: final / Resolution: 1.8→23.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2240 0 43 171 2454
Biso mean--40.29 34.37 -
Num. residues----280
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d820SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC8
X-RAY DIFFRACTIONt_gen_planes375HARMONIC8
X-RAY DIFFRACTIONt_it2364HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion283SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2869SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2364HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3200HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion2.54
X-RAY DIFFRACTIONt_other_torsion16.09
LS refinement shellResolution: 1.8→1.86 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.183 128 5 %
Rwork0.1882 2430 -
all0.188 2558 -
obs--97.55 %

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