Related Experiment Video

Updated: Oct 1, 2025

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
09:07

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

6.5K

Ligands with different dimeric configurations potently activate the EphA2 receptor and reveal its potential for

Maricel Gomez-Soler1, Marina P Gehring1, Bernhard C Lechtenberg2

  • 1Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.

Iscience
|March 4, 2022
PubMed

Insights

Researchers engineered dimeric peptides to control EphA2 receptor tyrosine kinase (RTK) signaling. These biased ligands show distinct potency and efficacy, offering a new therapeutic strategy for pathologies involving EphA2.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Pharmacology

Background:

  • The EphA2 receptor tyrosine kinase (RTK) plays a dual role in cancer and other diseases, activating diverse signaling pathways.
  • Developing specific, potent, and biased ligands for EphA2 is crucial for targeted therapeutic interventions.

Purpose of the Study:

  • To engineer dimeric peptides with distinct geometric configurations to differentially modulate EphA2 signaling.
  • To investigate the potency, efficacy, and biased signaling of these novel dimeric ligands compared to monomeric peptides and ephrinA1-Fc.

Main Methods:

  • Design and synthesis of dimeric peptides based on EphA2-specific monomeric peptides in three geometric arrangements.
  • Assessment of EphA2 clustering, autophosphorylation, and downstream signaling.
  • Comparative analysis of ligand potency, efficacy, and signaling bias against ephrinA1-Fc.

Main Results:

  • Engineered dimeric peptides induced EphA2 clustering, autophosphorylation, and signaling with sub-nanomolar potency.
  • Different dimeric configurations exhibited distinct potency and efficacy in modulating specific EphA2 signaling responses.
  • The dimeric peptides demonstrated biased signaling compared to ephrinA1-Fc, mediated by different mechanisms.

Conclusions:

  • Dimeric peptide ligands can be engineered to achieve high potency and prolonged EphA2 receptor residence time.
  • Distinct geometric configurations of dimeric peptides allow for differential modulation of EphA2 signaling pathways.
  • These findings provide a proof-of-concept for developing targeted therapies by precisely controlling EphA2 signaling.
Keywords:
BiochemistryMolecular biologyMolecular interaction

More Related Videos

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

8.8K
Oligomerization Dynamics of Cell Surface Receptors in Living Cells by Total Internal Reflection Fluorescence Microscopy Combined with Number and Brightness Analysis10:43

Oligomerization Dynamics of Cell Surface Receptors in Living Cells by Total Internal Reflection Fluorescence Microscopy Combined with Number and Brightness Analysis

Published on: November 6, 2019

6.9K

Related Concept Videos

The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
2.5K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
11.5K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.6K
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
6.0K
Amplifying Signals via Second Messengers01:15

Amplifying Signals via Second Messengers

Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces...
7.3K
Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
80.4K