title: Structures of Ebola virus GP and sGP in complex with therapeutic antibodies.
abstract: The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene.
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Jesper
authors: J
authors: Pallesen
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Charles D
authors: CD
authors: Murin
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Natalia
authors: N
authors: de Val
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Christopher A
authors: http://orcid.org/0000-0002-3364-3083
authors: CA
authors: Cottrell
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Kathryn M
authors: KM
authors: Hastie
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Hannah L
authors: HL
authors: Turner
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Marnie L
authors: ML
authors: Fusco
authors: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: Andrew I
authors: AI
authors: Flyak
authors: Mapp Biopharmaceutical, San Diego, California 92121, USA.
authors: Larry
authors: http://orcid.org/0000-0002-6857-1024
authors: L
authors: Zeitlin
authors: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.|Department of Pediatrics, Vanderbilt University, Nashville, Tennessee 37232, USA.|Vanderbilt Vaccine Center, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: James E
authors: JE
authors: Crowe
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.|Scripps Translational Institute, La Jolla, California 92122, USA.
authors: Kristian G
authors: KG
authors: Andersen
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.|The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Erica Ollmann
authors: EO
authors: Saphire
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Andrew B
authors: AB
authors: Ward
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology; D000917:Antibody Formation; D003429:Cross Reactions; D020285:Cryoelectron Microscopy; D029043:Ebolavirus / Q000276:immunology* / Q000472:pathogenicity; D000939:Epitopes / Q000276:immunology; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000821:virology; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008961:Models, Structural; D009154:Mutation; D055503:Protein Multimerization; D016415:Sequence Alignment; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D014764:Viral Proteins; C000594176:ZMapp