Plasticity of the 340-loop in influenza neuraminidase offers new insight for antiviral drug development

• Main Authors: Han, Nanyu, Ng, Justin Tze Yang, Li, Yanpeng, Mu, Yuguang, Huang, Zunxi
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2021
• Subjects: Science::Biological sciences; Influenza; Neuraminidase
• Online Access: https://hdl.handle.net/10356/146355
• Institution: Nanyang Technological University

The recently discovered 340-cavity in influenza neuraminidase (NA) N6 and N7 subtypes has introduced new possibilities for rational structure-based drug design. However, the plasticity of the 340-loop (residues 342-347) and the role of the 340-loop in NA activity and substrate binding have not been deeply exploited. Here, we investigate the mechanism of 340-cavity formation and demonstrate for the first time that seven of nine NA subtypes are able to adopt an open 340-cavity over 1.8 μs total molecular dynamics simulation time. The finding that the 340-loop plays a role in the sialic acid binding pathway suggests that the 340-cavity can function as a druggable pocket. Comparing the open and closed conformations of the 340-loop, the side chain orientation of residue 344 was found to govern the formation of the 340-cavity. Additionally, the conserved calcium ion was found to substantially influence the stability of the 340-loop. Our study provides dynamical evidence supporting the 340-cavity as a druggable hotspot at the atomic level and offers new structural insight in designing antiviral drugs.