@article{b03dd4e3ce974aa3ac345a0073b71f84,
title = "Computational design of proteins targeting the conserved stem region of influenza hemagglutinin",
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.",
author = "Fleishman, {Sarel J.} and Whitehead, {Timothy A.} and Ekiert, {Damian C.} and Cyrille Dreyfus and Corn, {Jacob E.} and Strauch, {Eva Maria} and Wilson, {Ian A.} and David Baker",
note = "Computational designs were generated on resources generously provided by participants of Rosetta @ Home and the Argonne National Leadership Computing Facility. We thank J. L. Gallaher for protein preparation. S.J.F. was supported by a long-term fellowship from the Human Frontier Science Program, J.E.C. was supported by the Jane Coffin Childs Memorial Fund, and E.M.S. by a career development award from the National Institute of Allergy and Infectious Diseases, NIH, AI057141. Research in the Baker laboratory was supported by grants from the Defense Advanced Research Projects Agency, the NIH yeast resource center, the Defense Threat Reduction Agency, and the Howard Hughes Medical Institute and in the Wilson laboratory by NIH AI058113, predoctoral fellowships from the Achievement Rewards for College Scientists Foundation and the NIH Molecular Evolution Training Program GM080209 (D.C.E.), and the Skaggs Institute for Chemical Biology. X-ray diffraction data sets were collected at the Stanford Synchrotron Radiation Lightsource beamline 9-2 and at the Advanced Photon Source (APS) beamline 23ID-B (GM/CA-CAT). The GM/CA CAT 23-ID-B beamline has been funded in whole or in part with federal funds from National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Science, NIH (Y1-GM-1104). Use of the APS was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357. Coordinates and structure factors were deposited in the Protein Data Bank as entry 3R2X.",
year = "2011",
month = may,
day = "13",
doi = "https://doi.org/10.1126/science.1202617",
language = "الإنجليزيّة",
volume = "332",
pages = "816--821",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6031",
}