title: Structure of the extracellular domain of matrix protein 2 of influenza A virus in complex with a protective monoclonal antibody.
abstract: The extracellular domain of influenza A virus matrix protein 2 (M2e) is conserved and is being evaluated as a quasiuniversal influenza A vaccine candidate. We describe the crystal structure at 1.6 Å resolution of M2e in complex with the Fab fragment of an M2e-specific monoclonal antibody that protects against influenza A virus challenge. This antibody binds M2 expressed on the surfaces of cells infected with influenza A virus. Five out of six complementary determining regions interact with M2e, and three highly conserved M2e residues are critical for this interaction. In this complex, M2e adopts a compact U-shaped conformation stabilized in the center by the highly conserved tryptophan residue in M2e. This is the first description of the three-dimensional structure of M2e.
  
  
  OBJECTIVE
  M2e of influenza A is under investigation as a universal influenza A vaccine, but its three-dimensional structure is unknown. We describe the structure of M2e stabilized with an M2e-specific monoclonal antibody that recognizes natural M2. We found that the conserved tryptophan is positioned in the center of the U-shaped structure of M2e and stabilizes its conformation. The structure also explains why previously reported in vivo escape viruses, selected with a similar monoclonal antibody, carried proline residue substitutions at position 10 in M2.
authors.affiliation: Department of Biotechnology & Bioinformatics, College of Science & Technology, Korea University, Sejong, South Korea Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Ki Joon
authors.initials: KJ
authors.lastname: Cho
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Schepens
authors.affiliation: Department of Biotechnology & Bioinformatics, College of Science & Technology, Korea University, Sejong, South Korea.
authors.forename: Jong Hyeon
authors.initials: JH
authors.lastname: Seok
authors.affiliation: Department of Biotechnology & Bioinformatics, College of Science & Technology, Korea University, Sejong, South Korea.
authors.forename: Sella
authors.initials: S
authors.lastname: Kim
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Kenny
authors.initials: K
authors.lastname: Roose
authors.affiliation: Department of Biotechnology & Bioinformatics, College of Science & Technology, Korea University, Sejong, South Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Switch Laboratory, VIB, Leuven, Belgium Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Gallardo
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Evelien
authors.initials: E
authors.lastname: Van Hamme
authors.affiliation: Switch Laboratory, VIB, Leuven, Belgium Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.affiliation: Switch Laboratory, VIB, Leuven, Belgium Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Walter
authors.initials: W
authors.lastname: Fiers
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium xavier.saelens@irc.vib-ugent.be khkim@korea.ac.kr.
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
authors.affiliation: Department of Biotechnology & Bioinformatics, College of Science & Technology, Korea University, Sejong, South Korea xavier.saelens@irc.vib-ugent.be khkim@korea.ac.kr.
authors.forename: Kyung Hyun
authors.initials: KH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D000914:Antibodies, Viral / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D018360:Crystallography, X-Ray; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D011487:Protein Conformation; D014763:Viral Matrix Proteins / Q000737:chemistry*; D000086082:Viroporin Proteins
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D007140:Immunoglobulin Fab Fragments; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins