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- PDB-6d20: Crystal structure of Tyrosine-protein kinase receptor in complex ... -

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Basic information

Entry
Database: PDB / ID: 6d20
TitleCrystal structure of Tyrosine-protein kinase receptor in complex with 5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one and 5-{[2,4-dichloro-5-(pyridin-2-yl)benzene-1-carbonyl]amino}-N-(2-hydroxy-2-methylpropyl)-1-phenyl-1H-pyrazole-3-carboxamide Inhibitors
ComponentsHigh affinity nerve growth factor receptor
KeywordsTRANSFERASE/Inhibitor / Allosteric Inhibitor Complex Tyrosine 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-FQD / Chem-FQG / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.94 Å
AuthorsGreasley, S.E. / Johnson, E. / Kraus, M.L. / Cronin, C.N.
CitationJournal: J. Med. Chem. / Year: 2019
Title: Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors.
Authors: Bagal, S.K. / Omoto, K. / Blakemore, D.C. / Bungay, P.J. / Bilsland, J.G. / Clarke, P.J. / Corbett, M.S. / Cronin, C.N. / Cui, J.J. / Dias, R. / Flanagan, N.J. / Greasley, S.E. / Grimley, R. ...Authors: Bagal, S.K. / Omoto, K. / Blakemore, D.C. / Bungay, P.J. / Bilsland, J.G. / Clarke, P.J. / Corbett, M.S. / Cronin, C.N. / Cui, J.J. / Dias, R. / Flanagan, N.J. / Greasley, S.E. / Grimley, R. / Johnson, E. / Fengas, D. / Kitching, L. / Kraus, M.L. / McAlpine, I. / Nagata, A. / Waldron, G.J. / Warmus, J.S.
History
DepositionApr 12, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 2, 2018Provider: repository / Type: Initial release
Revision 1.1May 1, 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.year / _citation_author.identifier_ORCID
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)36,8813
Polymers36,1111
Non-polymers7712
Water4,035224
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14380 Å2
Unit cell
Length a, b, c (Å)113.940, 45.810, 79.490
Angle α, β, γ (deg.)90.000, 127.040, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-902-

HOH

21A-943-

HOH

31A-1082-

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: Insect cell expression vector pTIE1 (others)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-FQD / 5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one


Mass: 246.260 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H7FN2OS
#3: Chemical ChemComp-FQG / 5-{[2,4-dichloro-5-(pyridin-2-yl)benzene-1-carbonyl]amino}-N-(2-hydroxy-2-methylpropyl)-1-phenyl-1H-pyrazole-3-carboxamide


Mass: 524.399 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H23Cl2N5O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / 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: 2.29 Å3/Da / Density % sol: 46.35 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 8
Details: Well volume: 30.0 uL Well Ingredients: Polymer: 10.0 %w/v (6.0 uL of stock 50.0 %w/v) PEG 3350 Buffer: 16.0 %v/v (4.8 uL of stock 100.0 %v/v) tacsimate (pH 8.00) Organic (non-volatile): 10.0 ...Details: Well volume: 30.0 uL Well Ingredients: Polymer: 10.0 %w/v (6.0 uL of stock 50.0 %w/v) PEG 3350 Buffer: 16.0 %v/v (4.8 uL of stock 100.0 %v/v) tacsimate (pH 8.00) Organic (non-volatile): 10.0 %v/v (3.0 uL of stock 100.0 %v/v) Ethylene glycol Additive: 0.025 M (1.5 uL of stock 0.5 M) TCEP hydrochloride Plate setup temperature: 13 C Plate incubation temperature: 21 C Drop volume from well: 0.2 uL Drop protein volume: 0.4 uL Protein: 6.30 mg/mL (0.17 mM) Compound1: 1.00 mM (to aid crystallization). Compound23 (allostric inhibitor): 1.3ul 50mM compound23 DMSO stock in 133ul protein (0.50 mM)

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jan 29, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.94→50 Å / Num. obs: 23960 / % possible obs: 98.4 % / Redundancy: 3.8 % / Biso Wilson estimate: 23.6 Å2 / Rmerge(I) obs: 0.115 / Χ2: 1.035 / Net I/σ(I): 7.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.95-2.023.50.70822971.006197.1
2.02-2.13.70.52423971.065198
2.1-2.23.80.40223781.043198.1
2.2-2.313.80.32923621.053198.1
2.31-2.463.90.2623701.03198.3
2.46-2.653.80.19823981.03198.6
2.65-2.913.80.14324151.005198.8
2.91-3.333.80.09524051.034198.7
3.33-4.23.80.0624501.023199.2
4.2-503.70.04924881.055198.8

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Processing

Software
NameVersionClassification
HKL-2000data reduction
SCALEPACKdata scaling
BUSTERrefinement
PDB_EXTRACT3.24data extraction
BUSTERphasing
RefinementResolution: 1.94→45.47 Å / Cor.coef. Fo:Fc: 0.9489 / Cor.coef. Fo:Fc free: 0.9266 / SU R Cruickshank DPI: 0.147 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.152 / SU Rfree Blow DPI: 0.135 / SU Rfree Cruickshank DPI: 0.134
RfactorNum. reflection% reflectionSelection details
Rfree0.2072 1226 5.12 %RANDOM
Rwork0.1703 ---
obs0.1722 23957 97.77 %-
Displacement parametersBiso max: 111.56 Å2 / Biso mean: 28.71 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-0.8814 Å20 Å2-1.3706 Å2
2--4.721 Å20 Å2
3----5.6023 Å2
Refinement stepCycle: final / Resolution: 1.94→45.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 76 224 2652
Biso mean--23.85 39.79 -
Num. residues----296
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d841SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes53HARMONIC2
X-RAY DIFFRACTIONt_gen_planes403HARMONIC5
X-RAY DIFFRACTIONt_it2489HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion295SEMIHARMONIC5
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_contact2949SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2489HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3386HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3.29
X-RAY DIFFRACTIONt_other_torsion15.7
LS refinement shellResolution: 1.94→2.03 Å / Rfactor Rfree error: 0 / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2318 129 4.75 %
Rwork0.1966 2586 -
all0.1984 2715 -
obs--97.77 %

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