Exploring E-cadherin-peptidomimetics interaction using NMR and computational studies.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Cadherins are crucial for cell-cell adhesion, and their altered expression is linked to cancer progression.
• Peptidomimetic ligands targeting E-cadherin adhesion have shown potential in inhibiting cancer cell adhesion.

Purpose of the Study:

• To investigate the interaction between two peptidomimetic ligands and the extracellular domain of human E-cadherin.
• To elucidate the binding epitopes and dynamics of ligand-cadherin interactions using integrated experimental and computational approaches.

Main Methods:

• Saturation Transfer Difference Nuclear Magnetic Resonance (STD-NMR) experiments were performed on E-cadherin fragments at varying temperatures.
• Molecular docking and molecular dynamics simulations were employed to interpret NMR data and explore binding mechanisms at the atomic level.

Main Results:

• STD-NMR revealed distinct ligand binding epitopes and temperature-dependent effects based on the E-cadherin construct used.
• Simulations confirmed high dynamism in ligand-cadherin binding, correlating with protein flexibility, particularly in the adhesion arm.
• Evidence suggests the Asp1-Trp2 sequence of E-cadherin is involved in ligand binding events.

Conclusions:

• The study highlights the dynamic nature of peptidomimetic ligand interactions with E-cadherin.
• Understanding these interactions, especially the role of the adhesion arm, can guide the design of novel E-cadherin inhibitors for cancer therapy.
• Targeting both the Trp2 binding pocket and adhesion arm residues may prevent detrimental swap dimer formation in cancer cells.