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- PDB-8yte: Crystal Structure of TrkA D5 domain in complex with macrocyclic p... -

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Basic information

Entry
Database: PDB / ID: 8yte
TitleCrystal Structure of TrkA D5 domain in complex with macrocyclic peptide
Components
  • High affinity nerve growth factor receptor
  • Macrocyclic Peptide
KeywordsTRANSFERASE / cyclic peptide
Function / homology
Function and homology information


neurotrophin p75 receptor binding / behavioral response to formalin induced pain / olfactory nerve development / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / programmed cell death involved in cell development / response to hydrostatic pressure / neurotrophin receptor activity / mechanoreceptor differentiation ...neurotrophin p75 receptor binding / behavioral response to formalin induced pain / olfactory nerve development / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / programmed cell death involved in cell development / response to hydrostatic pressure / neurotrophin receptor activity / mechanoreceptor differentiation / nerve growth factor receptor activity / neurotrophin binding / GPI-linked ephrin receptor activity / nerve growth factor signaling pathway / axonogenesis involved in innervation / nerve growth factor binding / Sertoli cell development / Retrograde neurotrophin signalling / sympathetic nervous system development / NGF-independant TRKA activation / Signalling to p38 via RIT and RIN / ARMS-mediated activation / positive regulation of programmed cell death / positive regulation of Ras protein signal transduction / positive regulation of synapse assembly / PI3K/AKT activation / peptidyl-tyrosine autophosphorylation / Frs2-mediated activation / neurotrophin TRK receptor signaling pathway / detection of temperature stimulus involved in sensory perception of pain / positive regulation of GTPase activity / response to electrical stimulus / Signalling to RAS / detection of mechanical stimulus involved in sensory perception of pain / neuron development / positive regulation of synaptic transmission, glutamatergic / response to axon injury / transmembrane receptor protein tyrosine kinase activity / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / peptidyl-tyrosine phosphorylation / B cell differentiation / response to nutrient levels / positive regulation of NF-kappaB transcription factor activity / positive regulation of neuron projection development / circadian rhythm / receptor protein-tyrosine kinase / cellular response to nerve growth factor stimulus / cellular response to nicotine / kinase binding / recycling endosome membrane / positive regulation of angiogenesis / neuron projection development / late endosome membrane / late endosome / protein autophosphorylation / protein tyrosine kinase activity / neuron apoptotic process / early endosome membrane / spermatogenesis / negative regulation of neuron apoptotic process / learning or memory / early endosome / positive regulation of ERK1 and ERK2 cascade / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / response to xenobiotic stimulus / negative regulation of cell population proliferation / axon / neuronal cell body / dendrite / negative regulation of apoptotic process / cell surface / protein homodimerization activity / protein-containing complex / mitochondrion / 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 / 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
Similarity search - Domain/homology
AMINOMETHYLAMIDE / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsYamada, T. / Mihara, K. / Ueda, T. / Yamauchi, D. / Shimizu, M. / Ando, A. / Mayumi, K. / Nakata, Z. / Mikamiyama, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Hit to Lead Optimization of Macrocyclic Peptides as Novel Tropomyosin Receptor Kinase A Antagonists.
Authors: Yamada, T. / Mihara, K. / Ueda, T. / Yamauchi, D. / Shimizu, M. / Ando, A. / Mayumi, K. / Nakata, Z. / Mikamiyama, H.
History
DepositionMar 25, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 10, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2024Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 24, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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
B: Macrocyclic Peptide
C: High affinity nerve growth factor receptor
D: Macrocyclic Peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,39215
Polymers25,6854
Non-polymers70711
Water1,63991
1
A: High affinity nerve growth factor receptor
B: Macrocyclic Peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,1657
Polymers12,8422
Non-polymers3225
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-1 kcal/mol
Surface area6420 Å2
MethodPISA
2
C: High affinity nerve growth factor receptor
D: Macrocyclic Peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,2278
Polymers12,8422
Non-polymers3846
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2240 Å2
ΔGint1 kcal/mol
Surface area5960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.680, 66.972, 79.889
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: 11221.562 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK1, MTC, TRK, TRKA / Production host: Escherichia coli (E. coli)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Protein/peptide Macrocyclic Peptide


Mass: 1620.890 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GM1 / AMINOMETHYLAMIDE / GLYCINAMID


Mass: 74.082 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6N2O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 91 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.69 Å3/Da / Density % sol: 54.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.1 M Tris pH 8.5, , 25% w/v Polyethylene glycol 3,350, 0.2 M ammonium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Dec 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.26→50 Å / Num. obs: 13490 / % possible obs: 100 % / Redundancy: 5 % / CC1/2: 0.998 / CC star: 0.999 / Rmerge(I) obs: 0.055 / Rpim(I) all: 0.027 / Rrim(I) all: 0.061 / Χ2: 1.147 / Net I/σ(I): 12.7 / Num. measured all: 67505
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.26-2.344.70.30213280.9270.9810.1540.340.962100
2.34-2.4350.2413100.9580.9890.1190.2680.90199.9
2.43-2.5550.19613130.9710.9920.0970.2190.885100
2.55-2.685.10.16313300.9790.9950.080.1820.891100
2.68-2.855.10.12413270.9870.9970.0610.1380.869100
2.85-3.075.10.08313490.9940.9980.040.0920.892100
3.07-3.385.10.05413320.9970.9990.0260.060.888100
3.38-3.865.10.03613580.99810.0170.040.856100
3.86-4.875.10.02413720.99910.0120.0270.747100
4.87-504.80.02914710.9960.9990.0150.0333.52899.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0218refinement
HKL-2000data scaling
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1WWA

1wwa


Resolution: 2.26→50 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.912 / SU B: 5.744 / SU ML: 0.141 / Cross valid method: THROUGHOUT / ESU R: 0.266 / ESU R Free: 0.219 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24947 609 4.5 %RANDOM
Rwork0.19668 ---
obs0.19891 12839 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.8 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å2-0 Å20 Å2
2--0.51 Å2-0 Å2
3----0.13 Å2
Refinement stepCycle: 1 / Resolution: 2.26→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1727 0 46 91 1864
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0191827
X-RAY DIFFRACTIONr_bond_other_d0.0010.021583
X-RAY DIFFRACTIONr_angle_refined_deg1.2351.9262470
X-RAY DIFFRACTIONr_angle_other_deg0.7033.0013650
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2255220
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.22123.37383
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.15615231
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.956156
X-RAY DIFFRACTIONr_chiral_restr0.0710.2262
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212046
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02420
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_it1.5062.99890
X-RAY DIFFRACTIONr_mcbond_other1.5042.991889
X-RAY DIFFRACTIONr_mcangle_it2.5824.4681106
X-RAY DIFFRACTIONr_mcangle_other2.5814.4681107
X-RAY DIFFRACTIONr_scbond_it1.4163.153937
X-RAY DIFFRACTIONr_scbond_other1.4153.153937
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.2494.6491365
X-RAY DIFFRACTIONr_long_range_B_refined4.0233.5941826
X-RAY DIFFRACTIONr_long_range_B_other3.98833.5821817
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.262→2.32 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.376 44 -
Rwork0.252 901 -
obs--96.43 %

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