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

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Basic information

Entry
Database: PDB / ID: 6dki
TitleCrystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 19.
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor Tyrosine kinase / TRANSFERASE / pan-Trk Kinase / Treatment for pain / 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 / response to axon injury / Signalling to RAS / neuron development / detection of mechanical stimulus involved in sensory perception of pain / peptidyl-tyrosine autophosphorylation / response to electrical stimulus / transmembrane receptor protein tyrosine kinase activity / B cell differentiation / positive regulation of synaptic transmission, glutamatergic / response to nutrient levels / positive regulation of GTPase activity / cellular response to nerve growth factor stimulus / axon guidance / receptor protein-tyrosine kinase / kinase binding / positive regulation of neuron projection development / cellular response to nicotine / peptidyl-tyrosine phosphorylation / circadian rhythm / positive regulation of angiogenesis / recycling endosome membrane / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / early endosome / learning or memory / receptor complex / endosome membrane / positive regulation of protein phosphorylation / response to xenobiotic stimulus / 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
5-phenylthieno[2,3-d]pyrimidin-4(3H)-one / Chem-GOD / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.11 Å
AuthorsGreasley, S.E. / Johnson, E. / Kraus, M.L. / Cronin, C.N.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.
Authors: Bagal, S.K. / Andrews, M. / Bechle, B.M. / Bian, J. / Bilsland, J. / Blakemore, D.C. / Braganza, J.F. / Bungay, P.J. / Corbett, M.S. / Cronin, C.N. / Cui, J.J. / Dias, R. / Flanagan, N.J. / ...Authors: Bagal, S.K. / Andrews, M. / Bechle, B.M. / Bian, J. / Bilsland, J. / Blakemore, D.C. / Braganza, J.F. / Bungay, P.J. / Corbett, M.S. / Cronin, C.N. / Cui, J.J. / Dias, R. / Flanagan, N.J. / Greasley, S.E. / Grimley, R. / James, K. / Johnson, E. / Kitching, L. / Kraus, M.L. / McAlpine, I. / Nagata, A. / Ninkovic, S. / Omoto, K. / Scales, S. / Skerratt, S.E. / Sun, J. / Tran-Dube, M. / Waldron, G.J. / Wang, F. / Warmus, J.S.
History
DepositionMay 29, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 15, 2018Group: 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.identifier_ORCID / _citation_author.name
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)36,8133
Polymers36,1111
Non-polymers7032
Water1,74797
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)113.640, 45.510, 79.320
Angle α, β, γ (deg.)90.00, 126.56, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-904-

HOH

21A-957-

HOH

31A-965-

HOH

41A-975-

HOH

51A-987-

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: 36110.504 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)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-22L / 5-phenylthieno[2,3-d]pyrimidin-4(3H)-one


Mass: 228.270 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H8N2OS
#3: Chemical ChemComp-GOD / 6-amino-5-{[(3S)-4,4-difluoro-1-{[4-(trifluoromethoxy)phenyl]acetyl}pyrrolidin-3-yl]oxy}-N-methylpyridine-3-carboxamide


Mass: 474.381 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19F5N4O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / 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: 2.28 Å3/Da / Density % sol: 46.08 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 8
Details: Well volume: 20.0 uL Well Ingredients: Polymer: 9.0 %w/v (3.6 uL of stock 50.0 %w/v) PEG 3350 Buffer: 15.8 %v/v (3.16 uL of stock 100.0 %v/v) tacsimate (pH 8.00) Additive: 0.025 M (5.0 uL of ...Details: Well volume: 20.0 uL Well Ingredients: Polymer: 9.0 %w/v (3.6 uL of stock 50.0 %w/v) PEG 3350 Buffer: 15.8 %v/v (3.16 uL of stock 100.0 %v/v) tacsimate (pH 8.00) Additive: 0.025 M (5.0 uL of stock 0.1 M) TCEP hydrochloride Plate setup temperature: 13 C Plate incubation temperature: 21 C Drop volume from well: 0.01 uL Drop protein volume: 0.2 uL Protein: 6.30 mg/mL

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.11→40.73 Å / Num. obs: 18843 / % possible obs: 99 % / Redundancy: 3.3 % / Biso Wilson estimate: 37.38 Å2 / Rsym value: 0.054 / Net I/σ(I): 12.9
Reflection shellResolution: 2.11→2.22 Å / Redundancy: 3.3 % / Num. unique obs: 2746 / Rsym value: 0.396 / % possible all: 99.7

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
SCALAdata scaling
Cootmodel building
BUSTERphasing
RefinementResolution: 2.11→40.73 Å / Cor.coef. Fo:Fc: 0.9491 / Cor.coef. Fo:Fc free: 0.9306 / SU R Cruickshank DPI: 0.199 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.197 / SU Rfree Blow DPI: 0.169 / SU Rfree Cruickshank DPI: 0.171
RfactorNum. reflection% reflectionSelection details
Rfree0.227 966 5.14 %RANDOM
Rwork0.1837 ---
obs0.186 18784 98.84 %-
Displacement parametersBiso mean: 39.71 Å2
Baniso -1Baniso -2Baniso -3
1--0.6636 Å20 Å2-0.4987 Å2
2--1.4264 Å20 Å2
3----0.7628 Å2
Refinement stepCycle: 1 / Resolution: 2.11→40.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2252 0 49 97 2398
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012389HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.973261HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d825SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes51HARMONIC2
X-RAY DIFFRACTIONt_gen_planes396HARMONIC5
X-RAY DIFFRACTIONt_it2389HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.2
X-RAY DIFFRACTIONt_other_torsion16.65
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion284SEMIHARMONIC5
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_contact2683SEMIHARMONIC4
LS refinement shellResolution: 2.11→2.24 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2412 170 5.63 %
Rwork0.1946 2850 -
all0.1972 3020 -
obs--98.84 %

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