Details

Autor(en) / Beteiligte

• Ellis, Daniel
• Lederhofer, Julia
• Acton, Oliver J
• Tsybovsky, Yaroslav
• Kephart, Sally
• Yap, Christina
• Gillespie, Rebecca A
• Creanga, Adrian
• Olshefsky, Audrey
• Stephens, Tyler
• Pettie, Deleah
• Murphy, Michael
• Sydeman, Claire
• Ahlrichs, Maggie
• Chan, Sidney
• Borst, Andrew J
• Park, Young-Jun
• Lee, Kelly K
• Graham, Barney S
• Veesler, David
• King, Neil P
• Kanekiyo, Masaru

Titel

Structure-based design of stabilized recombinant influenza neuraminidase tetramers

Ist Teil von

• Nature communications, 2022-04, Vol.13 (1), p.1825-1825, Article 1825

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an "open" state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We use homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the "closed" state, yielding two near-atomic resolution structures of NA by cryo-EM. In addition to enhancing thermal stability, conformational stabilization improves affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. Stabilized NAs can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, and establish design strategies for reinforcing the conformational integrity of recombinant NA proteins.