Complex of a protective antibody with its Ebola virus GP peptide epitope: unusual features of a V lambda x light chain.
13F6-1-2 is a murine monoclonal antibody that recognizes the heavily glycosylated mucin-like domain of the Ebola virus virion-attached glycoprotein (GP) and protects animals against lethal viral challenge. Here we present the crystal structure, at 2.0 A, of 13F6-1-2 in complex with its Ebola virus GP peptide epitope. The GP peptide binds in an extended conformation, anchored primarily by interactions with the heavy chain. Two GP residues, Gln P406 and Arg P409, make extensive side-chain hydrogen bond and electrostatic interactions with the antibody and are likely critical for recognition and affinity. The 13F6-1-2 antibody utilizes a rare V lambda(x) light chain. The three light-chain complementarity-determining regions do not adopt canonical conformations and represent new classes of structures distinct from V kappa and other V lambda light chains. In addition, although V lambda(x) had been thought to confer specificity, all light-chain contacts are mediated through germ-line-encoded residues. This structure of an antibody that protects against the Ebola virus now provides a framework for humanization and development of a postexposure immunotherapeutic.
Lee
Jeffrey E
JE
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Kuehne
Ana
A
Abelson
Dafna M
DM
Fusco
Marnie L
ML
Hart
Mary Kate
MK
Saphire
Erica Ollmann
EO
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D001483:Base Sequence; D018388:Codon, Terminator; D004220:Disulfides / Q000737:chemistry; D029043:Ebolavirus / Q000737:chemistry*; D000939:Epitopes; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000737:chemistry* / Q000235:genetics; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D020349:Surface Plasmon Resonance
D000911:Antibodies, Monoclonal; D018388:Codon, Terminator; D004220:Disulfides; D000939:Epitopes; D006023:Glycoproteins; D007140:Immunoglobulin Fab Fragments; D007146:Immunoglobulin lambda-Chains; D001120:Arginine