Computational design of proteins targeting the conserved stem region of influenza hemagglutinin

TitleComputational design of proteins targeting the conserved stem region of influenza hemagglutinin
Publication TypeJournal Article
Year of Publication2011
AuthorsFleishman, S. J., Whitehead T. A., Ekiert D. C., Dreyfus C., Corn J. E., Strauch E. - M., Wilson I. A., & Baker D.
JournalScience
Volume332
Issue6031
Pagination816-21
Date Published2011 May 13
ISSN1095-9203
KeywordsPrimary Publication
Abstract

We describe a general computational method for designing proteins that bind a surface patch of interest on a target macromolecule. Favorable interactions between disembodied amino acid residues and the target surface are identified and used to anchor de novo designed interfaces. The method was used to design proteins that bind a conserved surface patch on the stem of the influenza hemagglutinin (HA) from the 1918 H1N1 pandemic virus. After affinity maturation, two of the designed proteins, HB36 and HB80, bind H1 and H5 HAs with low nanomolar affinity. Further, HB80 inhibits the HA fusogenic conformational changes induced at low pH. The crystal structure of HB36 in complex with 1918/H1 HA revealed that the actual binding interface is nearly identical to that in the computational design model. Such designed binding proteins may be useful for both diagnostics and therapeutics.

Alternate JournalScience
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