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- PDB-5jr2: Crystal structure of the EphA4 LBD in complex with APYd3 peptide ... -

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Basic information

Entry
Database: PDB / ID: 5jr2
TitleCrystal structure of the EphA4 LBD in complex with APYd3 peptide inhibitor
Components
  • APYd3 peptide
  • Ephrin type-A receptor 4
KeywordsTRANSFERASE/INHIBITOR / receptor tyrosine kinase / peptide inhibitor / ephrin / ALS / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


DH domain binding / neuron projection fasciculation / positive regulation of Rho guanyl-nucleotide exchange factor activity / corticospinal tract morphogenesis / regulation of astrocyte differentiation / negative regulation of proteolysis involved in protein catabolic process / neuron projection guidance / nephric duct morphogenesis / regulation of synapse pruning / fasciculation of sensory neuron axon ...DH domain binding / neuron projection fasciculation / positive regulation of Rho guanyl-nucleotide exchange factor activity / corticospinal tract morphogenesis / regulation of astrocyte differentiation / negative regulation of proteolysis involved in protein catabolic process / neuron projection guidance / nephric duct morphogenesis / regulation of synapse pruning / fasciculation of sensory neuron axon / fasciculation of motor neuron axon / synapse pruning / negative regulation of cellular response to hypoxia / negative regulation of axon regeneration / positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process / glial cell migration / transmembrane-ephrin receptor activity / PH domain binding / GPI-linked ephrin receptor activity / regulation of modification of synaptic structure / negative regulation of epithelial to mesenchymal transition / regulation of dendritic spine morphogenesis / negative regulation of cell adhesion / motor neuron axon guidance / adult walking behavior / adherens junction organization / positive regulation of dendrite morphogenesis / EPH-Ephrin signaling / Somitogenesis / regulation of axonogenesis / positive regulation of amyloid-beta formation / cochlea development / regulation of GTPase activity / EPHA-mediated growth cone collapse / negative regulation of long-term synaptic potentiation / positive regulation of cell adhesion / EPH-ephrin mediated repulsion of cells / ephrin receptor signaling pathway / positive regulation of protein tyrosine kinase activity / axon terminus / axonal growth cone / protein tyrosine kinase binding / ephrin receptor binding / negative regulation of cell migration / dendritic shaft / filopodium / axon guidance / postsynaptic density membrane / adherens junction / Schaffer collateral - CA1 synapse / neuromuscular junction / negative regulation of ERK1 and ERK2 cascade / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / cellular response to amyloid-beta / negative regulation of neuron projection development / presynaptic membrane / amyloid-beta binding / kinase activity / perikaryon / early endosome membrane / protein tyrosine kinase activity / mitochondrial outer membrane / dendritic spine / protein autophosphorylation / negative regulation of translation / protein stabilization / cell adhesion / protein kinase activity / positive regulation of cell migration / axon / glutamatergic synapse / dendrite / positive regulation of cell population proliferation / 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 2 transmembrane 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) / Galactose-binding domain-like / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Jelly Rolls / 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 / Sandwich / Mainly Beta
Similarity search - Domain/homology
HEXANE-1,6-DIOL / Ephrin type-A receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsLechtenberg, B.C. / Olson, E.J. / Pasquale, E.B. / Dawson, P.E. / Riedl, S.J.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS087070 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA030199 United States
National Science Foundation (NSF, United States)DGE-1346837 United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability.
Authors: Olson, E.J. / Lechtenberg, B.C. / Zhao, C. / Rubio de la Torre, E. / Lamberto, I. / Riedl, S.J. / Dawson, P.E. / Pasquale, E.B.
History
DepositionMay 5, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2016Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Derived calculations / Refinement description
Category: pdbx_audit_support / pdbx_struct_oper_list / software
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.3Nov 27, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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: Ephrin type-A receptor 4
C: Ephrin type-A receptor 4
D: Ephrin type-A receptor 4
E: APYd3 peptide
F: APYd3 peptide
G: APYd3 peptide
H: APYd3 peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,02122
Polymers87,5758
Non-polymers1,44614
Water12,340685
1
A: Ephrin type-A receptor 4
E: APYd3 peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,4067
Polymers21,8942
Non-polymers5135
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2160 Å2
ΔGint-3 kcal/mol
Surface area10260 Å2
MethodPISA
2
B: Ephrin type-A receptor 4
F: APYd3 peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,5258
Polymers21,8942
Non-polymers6316
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2160 Å2
ΔGint-3 kcal/mol
Surface area10240 Å2
MethodPISA
3
C: Ephrin type-A receptor 4
G: APYd3 peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1044
Polymers21,8942
Non-polymers2102
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1910 Å2
ΔGint-2 kcal/mol
Surface area9810 Å2
MethodPISA
4
D: Ephrin type-A receptor 4
H: APYd3 peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,9863
Polymers21,8942
Non-polymers921
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1650 Å2
ΔGint-6 kcal/mol
Surface area10710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.137, 84.467, 127.894
Angle α, β, γ (deg.)90.00, 93.87, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Beg auth comp-ID: GLY / Beg label comp-ID: GLY / End auth comp-ID: ALA / End label comp-ID: ALA / Refine code: 0 / Auth seq-ID: 26 - 204 / Label seq-ID: 1 - 179

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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


Mass: 20489.143 Da / Num. of mol.: 4 / 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
APYd3 peptide


Mass: 1404.617 Da / Num. of mol.: 4 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical
ChemComp-HEZ / HEXANE-1,6-DIOL / 1,6-Hexanediol


Mass: 118.174 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C6H14O2
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 685 / 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: 46.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2 M MgCl2, 0.1 M Bis-Tris pH 6.5, 25% PEG 3,350, 3% 1,6-hexanediol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Dec 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.75→28.92 Å / Num. obs: 78825 / % possible obs: 99.3 % / Redundancy: 3.6 % / Biso Wilson estimate: 17.1 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.042 / Net I/σ(I): 17.9
Reflection shellResolution: 1.75→1.78 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.316 / Mean I/σ(I) obs: 3.1 / % possible all: 96.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
XDSMarch 1, 2015data scaling
Aimless0.5.17data scaling
PHASER2.5.7phasing
Coot0.8.2model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4W4Z

4w4z


Resolution: 1.75→28.92 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.942 / SU B: 4.697 / SU ML: 0.078 / Cross valid method: THROUGHOUT / ESU R: 0.121 / ESU R Free: 0.113 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20416 4103 5.2 %RANDOM
Rwork0.17036 ---
obs0.17209 74698 99.21 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1 Å
Displacement parametersBiso mean: 22.711 Å2
Baniso -1Baniso -2Baniso -3
1--0.13 Å20 Å2-0.07 Å2
2---0.04 Å2-0 Å2
3---0.18 Å2
Refinement stepCycle: 1 / Resolution: 1.75→28.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6077 0 96 685 6858
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.026683
X-RAY DIFFRACTIONr_bond_other_d0.0070.026210
X-RAY DIFFRACTIONr_angle_refined_deg1.5911.9619058
X-RAY DIFFRACTIONr_angle_other_deg1.322314311
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.635812
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.3124.146328
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.03151133
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8521551
X-RAY DIFFRACTIONr_chiral_restr0.090.2952
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.027702
X-RAY DIFFRACTIONr_gen_planes_other0.0060.021581
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_it1.321.4473225
X-RAY DIFFRACTIONr_mcbond_other1.3211.4463223
X-RAY DIFFRACTIONr_mcangle_it2.212.1554082
X-RAY DIFFRACTIONr_mcangle_other2.212.1554082
X-RAY DIFFRACTIONr_scbond_it1.7791.6673458
X-RAY DIFFRACTIONr_scbond_other1.7791.6673458
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.8052.4024977
X-RAY DIFFRACTIONr_long_range_B_refined6.15112.5717560
X-RAY DIFFRACTIONr_long_range_B_other6.15112.5747561
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A108220.08
12B108220.08
21A103020.1
22C103020.1
31A102480.11
32D102480.11
41B101620.11
42C101620.11
51B101870.11
52D101870.11
61C103530.07
62D103530.07
LS refinement shellResolution: 1.75→1.795 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.234 332 -
Rwork0.226 5345 -
obs--97.28 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.535-0.2620.27431.285-0.32520.9418-0.0122-0.06240.03510.1182-0.0281-0.0482-0.04440.00640.04030.0234-0.01-0.00320.01490.00310.0238-8.3621-5.8483137.239
20.44020.087-0.26091.2135-0.09650.717-0.00030.0297-0.0532-0.102-0.0516-0.07230.02360.01360.05190.03130.00820.00260.00660.00140.03655.8375-37.9877181.9642
30.5135-0.13510.15821.9511-0.23721.2670.0307-0.03590.00560.1526-0.0167-0.00750.06190.0751-0.0140.02270.0026-0.00240.01790.00830.01493.1435-45.7752146.0569
40.5267-0.1627-0.04681.4839-0.29281.11820.05360.09870.0266-0.1101-0.0757-0.0683-0.08320.07220.02210.02630.00490.00610.03160.02070.030717.35961.6479172.655
54.5793-1.1987-4.09251.79760.780810.05710.1518-0.1837-0.3501-0.00330.01230.04160.30820.0388-0.16420.0587-0.0117-0.03340.01210.02860.0754-11.3372-22.3666142.5893
64.89572.49834.49513.80730.90878.1934-0.01310.19990.2506-0.09880.12930.0705-0.31020.0803-0.11610.06380.00980.01990.0110.01790.07652.8196-21.4717176.6258
75.7917-0.8146-3.81683.1089-2.047910.31640.1132-0.1198-0.26610.03960.16010.15870.31140.1126-0.27330.09240.0141-0.02630.01380.00170.03863.279-62.5628152.6395
84.02841.29163.06631.88010.03179.5248-0.07780.05990.3346-0.0299-0.0335-0.0932-0.34030.14880.11130.0826-0.00190.01370.02020.02670.085218.670917.9149165.8087
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A26 - 204
2X-RAY DIFFRACTION2B26 - 204
3X-RAY DIFFRACTION3C26 - 204
4X-RAY DIFFRACTION4D26 - 204
5X-RAY DIFFRACTION5E1 - 13
6X-RAY DIFFRACTION6F1 - 13
7X-RAY DIFFRACTION7G1 - 13
8X-RAY DIFFRACTION8H1 - 13

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