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- PDB-8ytd: Crystal Structure of TrkA D5 domain in complex with two different... -

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Basic information

Entry
Database: PDB / ID: 8ytd
TitleCrystal Structure of TrkA D5 domain in complex with two different macrocyclic peptides
Components
  • (Macrocyclic Peptide) x 2
  • High affinity nerve growth factor receptor
KeywordsTRANSFERASE
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 / 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
High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.34 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

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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: Macrocyclic Peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,3787
Polymers15,1303
Non-polymers2484
Water90150
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2680 Å2
ΔGint-15 kcal/mol
Surface area7770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.374, 50.374, 143.959
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-522-

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: 11221.562 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: Escherichia coli (E. coli)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Protein/peptide Macrocyclic Peptide


Mass: 1676.957 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Protein/peptide Macrocyclic Peptide


Mass: 2231.513 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / 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: 3.03 Å3/Da / Density % sol: 59.4 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 25% v/v ethylene glycol

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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: May 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.34→50 Å / Num. obs: 8455 / % possible obs: 99.8 % / Redundancy: 9.3 % / CC1/2: 0.978 / CC star: 0.994 / Rmerge(I) obs: 0.044 / Rpim(I) all: 0.016 / Rrim(I) all: 0.047 / Χ2: 1.049 / Net I/σ(I): 20.2 / Num. measured all: 78245
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.34-2.429.10.3518020.9660.9910.1210.3720.86199.4
2.42-2.529.50.2898350.9780.9940.0980.3050.895100
2.52-2.649.50.2138110.9860.9970.0720.2250.864100
2.64-2.779.40.1488230.9920.9980.050.1570.901100
2.77-2.959.50.1028260.9950.9990.0350.1080.948100
2.95-3.189.40.0678310.9970.9990.0230.0710.943100
3.18-3.59.40.0488420.9980.9990.0160.050.99100
3.5-49.30.0358560.9970.9990.0120.0370.837100
4-5.049.20.0298770.99810.010.0310.669100
5.04-508.40.0339520.9550.9880.0140.0372.57898.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0218refinement
HKL-2000data scaling
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.34→47.55 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.901 / SU B: 6.946 / SU ML: 0.167 / Cross valid method: THROUGHOUT / ESU R: 0.292 / ESU R Free: 0.245 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27596 429 5.1 %RANDOM
Rwork0.21842 ---
obs0.2212 7979 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.21 Å2
Baniso -1Baniso -2Baniso -3
1-0.4 Å2-0 Å2-0 Å2
2--0.4 Å2-0 Å2
3----0.8 Å2
Refinement stepCycle: 1 / Resolution: 2.34→47.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1037 0 16 50 1103
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0191098
X-RAY DIFFRACTIONr_bond_other_d0.0010.02912
X-RAY DIFFRACTIONr_angle_refined_deg1.3691.9231479
X-RAY DIFFRACTIONr_angle_other_deg0.7523.0022100
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8555130
X-RAY DIFFRACTIONr_dihedral_angle_2_deg24.29423.06149
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.10615131
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.083153
X-RAY DIFFRACTIONr_chiral_restr0.0750.2153
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211221
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02255
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_it1.6072.855535
X-RAY DIFFRACTIONr_mcbond_other1.6022.85534
X-RAY DIFFRACTIONr_mcangle_it2.7434.248658
X-RAY DIFFRACTIONr_mcangle_other2.7414.254659
X-RAY DIFFRACTIONr_scbond_it1.7393.063563
X-RAY DIFFRACTIONr_scbond_other1.7383.063563
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.6794.499822
X-RAY DIFFRACTIONr_long_range_B_refined4.73932.8311133
X-RAY DIFFRACTIONr_long_range_B_other4.67732.7911127
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.341→2.401 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.354 33 -
Rwork0.262 573 -
obs--100 %

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