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

Sarel J. Fleishman, Timothy A. Whitehead, Damian C. Ekiert, Cyrille Dreyfus, Jacob E. Corn, Eva Maria Strauch, Ian A. Wilson, David Baker

Research output: Research - peer-reviewArticle

  • 297 Citations

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.

LanguageEnglish (US)
Pages816-821
Number of pages6
JournalScience
Volume332
Issue number6031
DOIs
StatePublished - May 13 2011
Externally publishedYes

Profile

Hemagglutinins
Protein Transport
Human Influenza
Proteins
H1N1 Subtype Influenza A Virus
Pandemics
Carrier Proteins
Amino Acids
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Fleishman, S. J., Whitehead, T. A., Ekiert, D. C., Dreyfus, C., Corn, J. E., Strauch, E. M., ... Baker, D. (2011). Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. Science, 332(6031), 816-821. DOI: 10.1126/science.1202617

Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. / Fleishman, Sarel J.; Whitehead, Timothy A.; Ekiert, Damian C.; Dreyfus, Cyrille; Corn, Jacob E.; Strauch, Eva Maria; Wilson, Ian A.; Baker, David.

In: Science, Vol. 332, No. 6031, 13.05.2011, p. 816-821.

Research output: Research - peer-reviewArticle

Fleishman, SJ, Whitehead, TA, Ekiert, DC, Dreyfus, C, Corn, JE, Strauch, EM, Wilson, IA & Baker, D 2011, 'Computational design of proteins targeting the conserved stem region of influenza hemagglutinin' Science, vol 332, no. 6031, pp. 816-821. DOI: 10.1126/science.1202617
Fleishman SJ, Whitehead TA, Ekiert DC, Dreyfus C, Corn JE, Strauch EM et al. Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. Science. 2011 May 13;332(6031):816-821. Available from, DOI: 10.1126/science.1202617
Fleishman, Sarel J. ; Whitehead, Timothy A. ; Ekiert, Damian C. ; Dreyfus, Cyrille ; Corn, Jacob E. ; Strauch, Eva Maria ; Wilson, Ian A. ; Baker, David. / Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. In: Science. 2011 ; Vol. 332, No. 6031. pp. 816-821
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