Demonstrating Ligandability of the LC3A and LC3B Adapter Interface

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Autophagy is a crucial cellular process involving lysosome-based degradation of cytosolic components.
• Atg8 family proteins, including LC3A and LC3B, are essential regulators of autophagy.
• Targeting autophagy proteins offers potential therapeutic strategies.

Purpose of the Study:

• To identify small molecule inhibitors for human LC3A and LC3B proteins.
• To explore the druggability of Atg8 family proteins.
• To lay the groundwork for developing novel autophagy modulators.

Main Methods:

• Screening of small molecule inhibitors against LC3A and LC3B.
• Structure-activity relationship (SAR) studies of 4-hydroxy coumarin derivatives.
• Crystallography to determine the binding mode of inhibitors.

Main Results:

• Novobiocin identified as a small molecule inhibitor of LC3A and LC3B.
• Demonstrated the druggability of LC3A and LC3B with nonpeptide inhibitors.
• Elucidated the binding interaction through crystal structure analysis.

Conclusions:

• The study presents the first nonpeptide inhibitors for Atg8 family proteins.
• These findings pave the way for developing advanced chemical probes for autophagy research.
• Potential applications include the development of autophagy-mediated degraders (AUTACs).