Sunitinib inhibits RNase L by destabilizing its active dimer conformation

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• RNase L is a pseudokinase crucial for innate immunity.
• Its ribonuclease activity is regulated by kinase inhibitors like sunitinib.
• Combined oncolytic virus and sunitinib show synergistic anticancer effects.

Purpose of the Study:

• To elucidate the mechanism by which sunitinib inhibits RNase L.
• To understand the structural basis of sunitinib's interaction with RNase L.

Main Methods:

• Crystal structure determination of RNase L with sunitinib and analogs.
• Molecular dynamics simulations.
• Dynamic light scattering experiments.

Main Results:

• Sunitinib binds to the ATP-binding pocket of RNase L.
• An unusual binding orientation was observed due to the αA helix.
• Sunitinib binding destabilized RNase L dimers, allosterically inhibiting ribonuclease activity.

Conclusions:

• Dimer destabilization is a viable strategy for RNase L inhibitor discovery.
• Targeting the ATP-binding pocket effectively modulates RNase L activity.
• This research provides insights into sunitinib's anticancer mechanism via RNase L inhibition.