Science. Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin

[Giuseppe]

See also about the same paper at Shiloh of FluTrackers.com http://www.flutrackers.com/forum/showthread.php?p=408205#post408205 post: :tiphat:

[Source: Science, full text: (LINK). Abstract, edited.]

<CITE><ABBR>Science</ABBR> 13 May 2011:
Vol. 332 no. 6031 pp. 816-821
DOI: 10.1126/science.1202617 </CITE>

• Research Article

Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin

1. Sarel J. Fleishman<SUP>1</SUP>,*,
2. Timothy A. Whitehead<SUP>1</SUP>,*,
3. Damian C. Ekiert<SUP>2</SUP>,*,
4. Cyrille Dreyfus<SUP>2</SUP>,
5. Jacob E. Corn<SUP>1</SUP>,<SUP>?</SUP>,
6. Eva-Maria Strauch<SUP>1</SUP>,
7. Ian A. Wilson<SUP>2</SUP>, and
8. David Baker<SUP>1</SUP>,<SUP>3</SUP>,<SUP>?</SUP>

Author Affiliations

1. <SUP>1</SUP>Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
2. <SUP>2</SUP>Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
3. <SUP>3</SUP>Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.

Author Notes

• ? Present address: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.

1. ?To whom correspondence should be addressed. E-mail: dabaker@uw.edu

1. * These authors contributed equally to this manuscript.

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.

• Received for publication 7 January 2011.
• Accepted for publication 8 April 2011.

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