@article{39a0d5efa73d4e1d869163672d2fbb3f,
title = "Structural basis for antibody-mediated neutralization of Lassa virus",
abstract = "The arenavirus Lassa causes severe hemorrhagic fever and a significant disease burden in West Africa every year. The glycoprotein, GPC, is the sole antigen expressed on the viral surface and the critical target for antibody-mediated neutralization. Here we present the crystal structure of the trimeric, prefusion ectodomain of Lassa GP bound to a neutralizing antibody from a human survivor at 3.2-angstrom resolution. The antibody extensively anchors two monomers together at the base of the trimer, and biochemical analysis suggests that it neutralizes by inhibiting conformational changes required for entry. This work illuminates pH-driven conformational changes in both receptor-binding and fusion subunits of Lassa virus, illustrates the unique assembly of the arenavirus glycoprotein spike, and provides a much-needed template for vaccine design against these threats to global health.",
author = "Hastie, {Kathryn M.} and Zandonatti, {Michelle A.} and Kleinfelter, {Lara M.} and Heinrich, {Megan L.} and Rowland, {Megan M.} and Kartik Chandran and Branco, {Luis M.} and Robinson, {James E.} and Garry, {Robert F.} and Saphire, {Erica Ollmann}",
note = "Funding Information: The authors acknowledge the Viral Hemorrhagic Fever Research Consortium, the Viral Hemorrhagic Fever Immunotherapeutic Consortium (VIC), and NIH grant 1U19AI109762-01 (E.O.S., K.C., J.E.R., L.M.B., and R.F.G); NIH grant R21 AI116112 (E.O.S.); NIH Training Program grant T32 GM007491 (L.M.K.); NIH contract HHSN272200900049C (J.E.R., E.O.S., R.F.G., and L.M.B.); an Investigators in Pathogenesis of Infectious Diseases award from the Burroughs Wellcome Fund (E.O.S.); and beamline 12-2 of the Stanford Synchrotron Radiation Lightsource (Palo Alto, CA), as well as beamlines 19-ID, 23-ID-B, and 23-ID-D of the Advanced Photon Source (Argonne, IL) for data collection. We are also grateful to S. Whelan, Harvard Medical School, for providing the LAMP1-Fc expression plasmid used in these studies. K.M.H. designed and cloned the constructs, produced recombinant protein, crystallized the complex, built and refined the model, performed the receptor-binding experiments, analyzed the data, and wrote the manuscript; M.A.Z. cloned the constructs and produced recombinant protein; L.M.K. and K.C. performed the VSV neutralization and fusion assays; J.E.R., L.M.B., M.L.H., M.M.R., and R.F.G generated and produced antibodies used throughout the studies; and E.O.S. analyzed the data and wrote the manuscript. All authors commented on the manuscript. Crystallographic structure factors and coordinates are deposited into the Protein Data Bank with accession number 5VK2. Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences, under contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institute of General Medical Sciences (NIGMS), NIH (including P41GM103393). This research used resources of the Advanced Photon Source, a DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-AC02-06CH11357. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Correspondence and requests for materials should be addressed to E.O.S.. This is manuscript 29458 from The Scripps Research Institute. Publisher Copyright: Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.",
year = "2017",
month = jun,
day = "2",
doi = "10.1126/science.aam7260",
language = "English (US)",
volume = "356",
pages = "923--928",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6341",
}