Structure-driven steric occlusion of BCL-2 by an RNA origami Traptamer

Area of Science:

• Biochemistry
• Nanotechnology
• Computational Biology

Background:

• The BCL-2 protein family promotes cancer cell survival and drug resistance.
• Existing small-molecule inhibitors face challenges with selectivity and resistance.
• Targeting protein-protein interactions (PPIs) is crucial for cancer therapy.

Purpose of the Study:

• To explore RNA origami nanostructures as a novel strategy for inhibiting cancer-driving PPIs.
• To identify specific RNA structures capable of targeting anti-apoptotic proteins.
• To establish a computational proof-of-concept for RNA-based steric inhibition.

Main Methods:

• In silico docking of 234 RNA structures against BCL-2 family proteins.
• Structural analysis of RNA-protein interactions, including hydrogen bonding and salt bridges.
• Normal Mode Analysis to assess binding interface stability and steric occlusion.
• Structural superposition and clash modeling to predict functional impact.

Main Results:

• A Traptamer (PDB ID: 8TVZ) was identified as a potent binder to BCL-2 family proteins.
• The Traptamer buries a significant portion of the protein surface, forming extensive interactions.
• Structural analysis indicates the Traptamer sterically occludes the BH3-binding groove and may inhibit BAX binding.
• Normal Mode Analysis suggests the Traptamer induces a stable steric blockade.

Conclusions:

• RNA origami nanostructures can be repurposed as selective, steric-based inhibitors of challenging PPIs.
• Traptamers offer a programmable framework for targeting cancer-driving protein interactions.
• This computational study provides a proof-of-concept for RNA-based cancer therapeutics.