Structure, dynamics and allostery in the Influenza A M2 protein with respect to sequence, protein-protein interactions, and small molecule inhibitors

• Applicant: Dr. Loren Andreas
• Subject Area: Structural Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557003994

The influenza M2 proton channel is the target of two approved drugs that inhibit conduction. This emphasizes the importance of the protein, however, there is widespread resistance to these treatments in circulating strains. We are working on the structural characterization of M2 proteins, including newly designed inhibitors. In this context, we discovered allosteric modulation of protein structure that depends on small molecules and sequence variant. We selected variants of M2, representing the vast majority of current strains, and propose studies involving compounds, as well as the protein M1, known to interact with M2. Magic angle spinning (MAS) NMR spectroscopy is an ideal tool to study M2 because the protein is particularly sensitive to its environment, and the method allows us to study the protein under near-native conditions in lipid bilayers. We propose a detailed characterization of the structural effects of drug binding, and of binding partners, to reveal the determinants of allosteric modulation, and its potential biological role. This will be correlated with functional measurements. We present initial data suggesting that the amino acid histidine engages in important interactions, and we hypothesize that these interactions may be correlated with function. The proposed novel measurements of full-length M2, together with native interaction partners in the membrane environment will impact our understanding of basic biological processes in an important virus, and also provide a foundation for future drug development.

• DFG Programme: Research Grants