@article{e378bdeb56d045f0a4d77d9416db37c0,
title = "Cross-neutralization of influenza A viruses mediated by a single antibody loop",
abstract = "Immune recognition of protein antigens relies on the combined interaction of multiple antibody loops, which provide a fairly large footprint and constrain the size and shape of protein surfaces that can be targeted. Single protein loops can mediate extremely high-affinity binding, but it is unclear whether such a mechanism is available to antibodies. Here we report the isolation and characterization of an antibody called C05, which neutralizes strains from multiple subtypes of influenza A virus, including H1, H2 and H3. X-ray and electron microscopy structures show that C05 recognizes conserved elements of the receptor-binding site on the haemagglutinin surface glycoprotein. Recognition of the haemagglutinin receptor-binding site is dominated by a single heavy-chain complementarity-determining region 3 loop, with minor contacts from heavy-chain complementarity-determining region 1, and is sufficient to achieve nanomolar binding with a minimal footprint. Thus, binding predominantly with a single loop can allow antibodies to target small, conserved functional sites on otherwise hypervariable antigens.",
author = "Ekiert, {Damian C.} and Kashyap, {Arun K.} and John Steel and Adam Rubrum and Gira Bhabha and Reza Khayat and Lee, {Jeong Hyun} and Dillon, {Michael A.} and O'Neil, {Ryann E.} and Faynboym, {Aleksandr M.} and Michael Horowitz and Lawrence Horowitz and Ward, {Andrew B.} and Peter Palese and Richard Webby and Lerner, {Richard A.} and Bhatt, {Ramesh R.} and Wilson, {Ian A.}",
note = "Funding Information: Acknowledgements We thank H. Tien and D. Marciano for automated crystal screening, the staff of the Advanced Photon Source (APS) GM/CA-CAT and Stanford Synchrotron Radiation Lightsource (SSRL) BL11-1 for beamline support, X. Dai and R. Stanfield for assistance with data collection and processing, M. Hothorn for assistance with ITC experiments, J. Paulson and D. Burton for comments and discussion, A. Estelles and R. Briante, L. Xu, S. Wang and D. Corn for technical support and P.Foremanfor assistance withanimalstudydesign.Thisprojectwas fundedinpart by National Institutes of Health (NIH) grant P01AI058113 (I.A.W.), a predoctoral fellowship from the Achievement Rewards for College Scientists Foundation (D.C.E.), grant GM080209 from the NIH Molecular Evolution Training Program (D.C.E.), the Skaggs Institute (I.A.W.), a career development fellowship from the Northeast Biodefense Center (U54-AI057158-Lipkin) (J.S.), National Institute of Allergy and Infectious Diseases (NIAID) grant U01AI070373 (R.W.), and Center for Research on Influenza Pathogenesis NIAID contract HHSN266200700010C (P.P.). Portions of this research were carried out at the SSRL, a national user facility operated by Stanford University on behalf of the US Department of Energy (DOE), Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH, National Center for Research Resources, Biomedical Technology Program, and the National Institute of General Medical Sciences (NIGMS). The GM/CA-CAT 23-ID-B beamline has been funded in whole or in part with federal funds from the National Cancer Institute (Y1-CO-1020) and NIGMS (Y1-GM-1104). Use of the APS was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357. The electron microscopy data presented here was collected at the National Resource for Automated Molecular Microscopy, which is supported by the NIH though the P41 program (RR017573) at the National Center for Research Resources. The JCSG is supported by NIH grant U54 GM094586. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS or the NIH. This is publication 21421 from The Scripps Research Institute.",
year = "2012",
month = sep,
day = "27",
doi = "10.1038/nature11414",
language = "English",
volume = "489",
pages = "526--532",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
number = "7417",
}