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- PDB-7ofv: NMR-guided design of potent and selective EphA4 agonistic ligands -

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Basic information

Entry
Database: PDB / ID: 7ofv
TitleNMR-guided design of potent and selective EphA4 agonistic ligands
Components
  • EphA4 agonist ligand
  • Ephrin type-A receptor 4
KeywordsTRANSFERASE / EphA4 / 150D4 / ephrin / RTK
Function / homology
Function and homology information


DH domain binding / neuron projection fasciculation / : / negative regulation of proteolysis involved in protein catabolic process / corticospinal tract morphogenesis / regulation of astrocyte differentiation / neuron projection guidance / nephric duct morphogenesis / fasciculation of sensory neuron axon / fasciculation of motor neuron axon ...DH domain binding / neuron projection fasciculation / : / negative regulation of proteolysis involved in protein catabolic process / corticospinal tract morphogenesis / regulation of astrocyte differentiation / neuron projection guidance / nephric duct morphogenesis / fasciculation of sensory neuron axon / fasciculation of motor neuron axon / synapse pruning / negative regulation of cellular response to hypoxia / negative regulation of axon regeneration / transmembrane-ephrin receptor activity / glial cell migration / positive regulation of amyloid precursor protein catabolic process / PH domain binding / regulation of modification of synaptic structure / GPI-linked ephrin receptor activity / regulation of synapse pruning / adherens junction organization / positive regulation of dendrite morphogenesis / regulation of dendritic spine morphogenesis / negative regulation of cell adhesion / motor neuron axon guidance / EPH-Ephrin signaling / innervation / adult walking behavior / regulation of GTPase activity / negative regulation of epithelial to mesenchymal transition / Somitogenesis / regulation of axonogenesis / positive regulation of amyloid-beta formation / EPHA-mediated growth cone collapse / positive regulation of intracellular signal transduction / negative regulation of long-term synaptic potentiation / cochlea development / EPH-ephrin mediated repulsion of cells / ephrin receptor signaling pathway / axonal growth cone / ephrin receptor binding / axon terminus / positive regulation of cell adhesion / axon guidance / protein tyrosine kinase binding / peptidyl-tyrosine phosphorylation / negative regulation of cell migration / dendritic shaft / positive regulation of JNK cascade / filopodium / adherens junction / neuromuscular junction / receptor protein-tyrosine kinase / postsynaptic density membrane / negative regulation of ERK1 and ERK2 cascade / Schaffer collateral - CA1 synapse / cellular response to amyloid-beta / kinase activity / negative regulation of neuron projection development / amyloid-beta binding / protein autophosphorylation / presynaptic membrane / protein tyrosine kinase activity / early endosome membrane / perikaryon / dendritic spine / negative regulation of neuron apoptotic process / mitochondrial outer membrane / protein kinase activity / cell adhesion / negative regulation of translation / protein stabilization / positive regulation of cell migration / axon / positive regulation of cell population proliferation / dendrite / glutamatergic synapse / cell surface / ATP binding / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Ephrin type-A receptor 4, SAM domain / Ephrin type-A receptor 4, ligand binding domain / Tyrosine-protein kinase ephrin type A/B receptor-like / Tyrosine-protein kinase ephrin type A/B receptor-like / Ephrin receptor type-A /type-B / Ephrin receptor ligand binding domain / Tyrosine-protein kinase, receptor class V, conserved site / Ephrin receptor, transmembrane domain / : / Ephrin receptor ligand binding domain ...Ephrin type-A receptor 4, SAM domain / Ephrin type-A receptor 4, ligand binding domain / Tyrosine-protein kinase ephrin type A/B receptor-like / Tyrosine-protein kinase ephrin type A/B receptor-like / Ephrin receptor type-A /type-B / Ephrin receptor ligand binding domain / Tyrosine-protein kinase, receptor class V, conserved site / Ephrin receptor, transmembrane domain / : / Ephrin receptor ligand binding domain / Ephrin type-A receptor 2 transmembrane domain / Receptor tyrosine kinase class V signature 1. / Receptor tyrosine kinase class V signature 2. / Eph receptor ligand-binding domain profile. / Ephrin receptor ligand binding domain / Putative ephrin-receptor like / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Galactose-binding-like domain superfamily / Fibronectin type III / Fibronectin type III 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 / Serine/Threonine protein kinases, catalytic domain / 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
ACETATE ION / Ephrin type-A receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.43 Å
AuthorsGanichkin, O.M. / Craig, T.K. / Baggio, C. / Pellecchia, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS107479 United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands.
Authors: Baggio, C. / Kulinich, A. / Dennys, C.N. / Rodrigo, R. / Meyer, K. / Ethell, I. / Pellecchia, M.
History
DepositionMay 5, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 11, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 25, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 31, 2024Group: Data collection / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_conn
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ephrin type-A receptor 4
B: EphA4 agonist ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2753
Polymers22,2162
Non-polymers591
Water5,441302
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint-1 kcal/mol
Surface area11200 Å2
Unit cell
Length a, b, c (Å)55.032, 55.032, 147.313
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Ephrin type-A receptor 4 / EPH-like kinase 8 / EK8 / hEK8 / Tyrosine-protein kinase TYRO1 / Tyrosine-protein kinase receptor SEK


Mass: 21259.100 Da / Num. of mol.: 1 / Mutation: C204A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EPHA4, HEK8, SEK, TYRO1 / Production host: Escherichia coli (E. coli)
References: UniProt: P54764, receptor protein-tyrosine kinase
#2: Protein/peptide EphA4 agonist ligand


Mass: 957.152 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 302 / 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: 2.47 Å3/Da / Density % sol: 50.11 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 4.5
Details: 0.10 M Na Acet, pH 4.50, 1.20 M K2HPO4, 0.80 M NaH2PO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 20, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.43→51.552 Å / Num. obs: 34710 / % possible obs: 93.8 % / Redundancy: 12.9 % / CC1/2: 1 / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.015 / Rrim(I) all: 0.055 / Rsym value: 0.053 / Net I/σ(I): 24.9
Reflection shellResolution: 1.43→1.544 Å / Redundancy: 4 % / Rmerge(I) obs: 0.883 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 1736 / CC1/2: 0.534 / Rpim(I) all: 0.48 / Rrim(I) all: 1.012 / Rsym value: 0.883 / % possible all: 57.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JR2

5jr2


Resolution: 1.43→51.547 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.951 / SU B: 3.147 / SU ML: 0.051 / Cross valid method: FREE R-VALUE / ESU R: 0.079 / ESU R Free: 0.077
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2065 1715 4.941 %
Rwork0.149 32995 -
all0.152 --
obs-34710 81.002 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 20.129 Å2
Baniso -1Baniso -2Baniso -3
1--0.066 Å20 Å20 Å2
2---0.066 Å20 Å2
3---0.131 Å2
Refinement stepCycle: LAST / Resolution: 1.43→51.547 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1558 0 4 302 1864
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0131611
X-RAY DIFFRACTIONr_bond_other_d0.0090.0181497
X-RAY DIFFRACTIONr_angle_refined_deg1.5621.7082190
X-RAY DIFFRACTIONr_angle_other_deg1.4611.6383437
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0875191
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.95722.29987
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg1.592201
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.4315.301282
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg35.574202
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8441511
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.6822010
X-RAY DIFFRACTIONr_dihedral_angle_other_6_deg16.29203
X-RAY DIFFRACTIONr_chiral_restr0.0830.2207
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021842
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02393
X-RAY DIFFRACTIONr_nbd_refined0.1730.2187
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1770.21313
X-RAY DIFFRACTIONr_nbtor_refined0.160.2753
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0710.2788
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1090.2183
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.060.25
X-RAY DIFFRACTIONr_nbd_other0.1290.262
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1540.235
X-RAY DIFFRACTIONr_mcbond_it2.9482.372756
X-RAY DIFFRACTIONr_mcbond_other2.8882.367754
X-RAY DIFFRACTIONr_mcangle_it3.1954.008949
X-RAY DIFFRACTIONr_mcangle_other3.1934.008950
X-RAY DIFFRACTIONr_scbond_it3.5552.773855
X-RAY DIFFRACTIONr_scbond_other3.5542.777856
X-RAY DIFFRACTIONr_scangle_it3.8984.4851241
X-RAY DIFFRACTIONr_scangle_other3.8974.491242
X-RAY DIFFRACTIONr_lrange_it4.43422.971786
X-RAY DIFFRACTIONr_lrange_other4.04321.4741706
X-RAY DIFFRACTIONr_rigid_bond_restr2.28333107
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.43-1.4670.33790.322080.3231050.6390.7756.98870.318
1.467-1.5070.316310.2895540.29130180.8260.81819.38370.285
1.507-1.5510.27600.2610640.26129460.8170.8538.15340.251
1.551-1.5990.258960.24118680.24228790.8360.86268.21810.226
1.599-1.6510.2571240.20425710.20627760.8770.89697.08210.184
1.651-1.7090.2421470.16925430.17326920.90.92899.92570.145
1.709-1.7730.2121460.13624860.1426320.9380.9531000.11
1.773-1.8460.1811240.12223680.12524920.9550.9611000.098
1.846-1.9280.2331130.11722900.12324030.940.9681000.094
1.928-2.0220.183980.10922330.11223310.9570.9741000.092
2.022-2.1310.191040.12420960.12722000.960.9711000.105
2.131-2.260.2031140.12119820.12520960.9490.9721000.103
2.26-2.4160.178900.12319050.12619950.9640.9711000.106
2.416-2.6090.213990.13517500.13918490.9520.9671000.117
2.609-2.8570.205740.14716350.14917090.9510.9641000.133
2.857-3.1930.181780.15414820.15515600.960.9671000.147
3.193-3.6840.184650.14713500.14914150.9690.9741000.148
3.684-4.5070.176660.14711270.14811930.9690.9731000.156
4.507-6.3490.227530.179110.1739640.9480.971000.19
6.349-51.5520.365240.2275720.2325960.8880.9421000.249

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