ArticleACS chemical biology2014
Development and structural analysis of a nanomolar cyclic peptide antagonist for the EphA4 receptor.
Article in ACS chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 39 citations in OpenAlex.
- Constrained β-Hairpins Targeting the EphA4 Ligand Binding Domain.Journal of medicinal chemistry · 2024Article
- Lipidation and PEGylation Strategies to Prolong theEuropean journal of medicinal chemistry · 2023Article
- More than skin deep: cyclic peptides as wound healing and cytoprotective compounds.Frontiers in cell and developmental biology · 2023Review
- A Consensus Gene Regulatory Network for Neurodegenerative Diseases Using Single-Cell RNA-Seq Data.Advances in experimental medicine and biology · 2023Article
- Ligands with different dimeric configurations potently activate the EphA2 receptor and reveal its potential for biased signaling.iScience · 2022Article
- Design of Protein Segments and Peptides for Binding to Protein Targets.Biodesign research · 2022Review
- Structural insights into EphA4 unconventional activation from prediction of the EphA4 and its complex with ribonuclease 1.American journal of cancer research · 2022Article
- NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands.Journal of medicinal chemistry · 2021Article
- Nogo-A-Δ20/EphA4 interaction antagonizes apoptosis of neural stem cells by integrating p38 and JNK MAPK signaling.Journal of molecular histology · 2021Article
- Bent Into Shape: Folded Peptides to Mimic Protein Structure and Modulate Protein Function.Peptide science (Hoboken, N.J.) · 2020Article
- Engineering nanomolar peptide ligands that differentially modulate EphA2 receptor signaling.The Journal of biological chemistry · 2019Article
- Genetically Encoded FRET Biosensor for Visualizing EphA4 Activity in Different Compartments of the Plasma Membrane.ACS sensors · 2019Article
- EphA4-ADAM10 Interplay Patterns the Cochlear Sensory Epithelium through Local Disruption of Adherens Junctions.iScience · 2019Article
- Therapeutic potential of targeting the Eph/ephrin signaling complex.The international journal of biochemistry & cell biology · 2018Review
- EphB4: A promising target for upper aerodigestive malignancies.Biochimica et biophysica acta. Reviews on cancer · 2018Review
- Modulatory Effects of a Novel Cyclized Peptide in Reducing the Expression of Markers Linked to Alzheimer's Disease.Frontiers in neuroscience · 2018Article
- SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration.The Journal of experimental medicine · 2017Article
- Identification and characterization of Nanobodies targeting the EphA4 receptor.The Journal of biological chemistry · 2017Article
- Targeting kinase signaling pathways with constrained peptide scaffolds.Pharmacology & therapeutics · 2017Review
- Potent and Selective EphA4 Agonists for the Treatment of ALS.Cell chemical biology · 2017Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
The EphA4 receptor is highly expressed in the nervous system, and recent findings suggest that its signaling activity hinders neural repair and exacerbates certain neurodegenerative processes. EphA4 has also been implicated in cancer progression. Thus, EphA4 inhibitors represent potential therapeutic leads and useful research tools to elucidate the role of EphA4 in physiology and disease. Here, we report the structure of a cyclic peptide antagonist, APY, in complex with the EphA4 ligand-binding domain (LBD), which represents the first structure of a cyclic peptide bound to a receptor tyrosine kinase. The structure shows that the dodecameric APY efficiently occupies the ephrin ligand-binding pocket of EphA4 and promotes a "closed" conformation of the surrounding loops. Structure-guided relaxation of the strained APY β-turn and amidation of the C terminus to allow an additional intrapeptide hydrogen bond yielded APY-βAla8.am, an improved APY derivative that binds to EphA4 with nanomolar affinity. APY-βAla8.am potently inhibits ephrin-induced EphA4 activation in cells and EphA4-dependent neuronal growth cone collapse, while retaining high selectivity for EphA4. The two crystal structures of APY and APY-βAla8.am bound to EphA4, in conjunction with secondary phage display screens, highlighted peptide residues that are essential for EphA4 binding as well as residues that can be modified. Thus, the APY scaffold represents an exciting prototype, particularly since cyclic peptides have potentially favorable metabolic stability and are emerging as an important class of molecules for disruption of protein-protein interactions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.