ArticleThe Journal of biological chemistry2019
Engineering nanomolar peptide ligands that differentially modulate EphA2 receptor signaling.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.
- Glioma Stem Cells as Promoter of Glioma Progression: A Systematic Review of Molecular Pathways and Targeted Therapies.International journal of molecular sciences · 2024Pooled it
- Mechanisms and Manifestations of Ligand Bias in Signaling: Focus on Receptor Tyrosine Kinases.Chemical reviews · 2026Review
- The Eph-ephrin system in neuropsychiatric and neurodevelopmental disorders.Journal of psychiatry & neuroscience : JPN · 2026Review
- Synthetic antibodies targeting EphA2 induce diverse signaling-competent clusters with differential activation.Protein science : a publication of the Protein Society · 2025Article
- Eph receptor signaling complexes in the plasma membrane.Trends in biochemical sciences · 2024Review
- Probing phosphorylation events in biological membranes: The transducer function.Biochimica et biophysica acta. Biomembranes · 2024Review
- Targeting the EphA2 pathway: could it be the way for bone sarcomas?Cell communication and signaling : CCS · 2024Review
- Quantitative and qualitative differences in the activation of a fibroblast growth factor receptor by different FGF ligands.Cytokine & growth factor reviews · 2024Review
- Article
- EphA2-specific microvesicles derived from tumor cells facilitate the targeted delivery of chemotherapeutic drugs for osteosarcoma therapy.Journal of nanobiotechnology · 2024Article
- Eph receptors and ephrins in cancer progression.Nature reviews. Cancer · 2024Review
- A computational and laboratory approach for the investigation of interactions of peptide conjugated natural terpenes with EpHA2 receptor.Journal of molecular modeling · 2023Article
- The Screening of Therapeutic Peptides for Anti-Inflammation through Phage Display Technology.International journal of molecular sciences · 2022Review
- Ligands with different dimeric configurations potently activate the EphA2 receptor and reveal its potential for biased signaling.iScience · 2022Article
- Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker.Nature communications · 2021Article
- Human herpesvirus 8 molecular mimicry of ephrin ligands facilitates cell entry and triggers EphA2 signaling.PLoS biology · 2021Article
- Structural and Functional Insights into the Transmembrane Domain Association of Eph Receptors.International journal of molecular sciences · 2021Review
- Article
- A cancer mutation promotes EphA4 oligomerization and signaling by altering the conformation of the SAM domain.The Journal of biological chemistry · 2021Article
- Neural network strategies for plasma membrane selection in fluorescence microscopy images.Biophysical journal · 2021Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The EPH receptor A2 (EphA2) tyrosine kinase plays an important role in a plethora of biological and disease processes, ranging from angiogenesis and cancer to inflammation and parasitic infections. EphA2 is therefore considered an important drug target. Two short peptides previously identified by phage display, named YSA and SWL, are widely used as EphA2-targeting agents owing to their high specificity for this receptor. However, these peptides have only modest (micromolar) potency. Lack of structural information on the binding interactions of YSA and SWL with the extracellular EphA2 ligand-binding domain (LBD) has for many years precluded structure-guided improvements. We now report the high-resolution (1.53-2.20 Å) crystal structures of the YSA peptide and several of its improved derivatives in complex with the EphA2 LBD, disclosing that YSA targets the ephrin-binding pocket of EphA2 and mimics binding features of the ephrin-A ligands. The structural information obtained enabled iterative peptide modifications conferring low nanomolar potency. Furthermore, contacts observed in the crystal structures shed light on how C-terminal features can convert YSA derivatives from antagonists to agonists that likely bivalently interact with two EphA2 molecules to promote receptor oligomerization, autophosphorylation, and downstream signaling. Consistent with this model, quantitative FRET measurements in live cells revealed that the peptide agonists promote the formation of EphA2 oligomeric assemblies. Our findings now enable rational strategies to differentially modify EphA2 signaling toward desired outcomes by using appropriately engineered peptides. Such peptides could be used as research tools to interrogate EphA2 function and to develop pharmacological leads.
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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.