Structural Basis for Marburg Virus Neutralization by a Cross-Reactive Human Antibody

Cell. 2015 Feb 26;160(5):904-912. doi: 10.1016/j.cell.2015.01.041.

Abstract

The filoviruses, including Marburg and Ebola, express a single glycoprotein on their surface, termed GP, which is responsible for attachment and entry of target cells. Filovirus GPs differ by up to 70% in protein sequence, and no antibodies are yet described that cross-react among them. Here, we present the 3.6 Å crystal structure of Marburg virus GP in complex with a cross-reactive antibody from a human survivor, and a lower resolution structure of the antibody bound to Ebola virus GP. The antibody, MR78, recognizes a GP1 epitope conserved across the filovirus family, which likely represents the binding site of their NPC1 receptor. Indeed, MR78 blocks binding of the essential NPC1 domain C. These structures and additional small-angle X-ray scattering of mucin-containing MARV and EBOV GPs suggest why such antibodies were not previously elicited in studies of Ebola virus, and provide critical templates for development of immunotherapeutics and inhibitors of entry.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Neutralizing / chemistry*
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / isolation & purification
  • Antibodies, Neutralizing / metabolism
  • Antibodies, Viral / chemistry
  • Antibodies, Viral / immunology
  • Antibodies, Viral / metabolism
  • Antigen-Antibody Complex / chemistry
  • Cell Line
  • Cross Reactions
  • Crystallography, X-Ray
  • Drosophila
  • Ebolavirus / chemistry
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / metabolism
  • Marburg Virus Disease / immunology
  • Marburgvirus / chemistry*
  • Marburgvirus / genetics
  • Marburgvirus / immunology
  • Models, Molecular
  • Molecular Sequence Data
  • Mucins / chemistry
  • Sequence Alignment
  • Viral Envelope Proteins / chemistry*
  • Viral Envelope Proteins / metabolism

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antigen-Antibody Complex
  • GP-protein, Marburg virus
  • Immunoglobulin Fab Fragments
  • Mucins
  • Viral Envelope Proteins
  • envelope glycoprotein, Ebola virus

Associated data

  • PDB/3X2D