title: Structural basis for abrogated binding between staphylococcal enterotoxin A superantigen vaccine and MHC-IIalpha.
abstract: Staphylococcal enterotoxins (SEs) are superantigenic protein toxins responsible for a number of life-threatening diseases. The X-ray structure of a staphylococcal enterotoxin A (SEA) triple-mutant (L48R, D70R, and Y92A) vaccine reveals a cascade of structural rearrangements located in three loop regions essential for binding the alpha subunit of major histocompatibility complex class II (MHC-II) molecules. A comparison of hypothetical model complexes between SEA and the SEA triple mutant with MHC-II HLA-DR1 clearly shows disruption of key ionic and hydrophobic interactions necessary for forming the complex. Extensive dislocation of the disulfide loop in particular interferes with MHC-IIalpha binding. The triple-mutant structure provides new insights into the loss of superantigenicity and toxicity of an engineered superantigen and provides a basis for further design of enterotoxin vaccines.
authors.affiliation: Lawrence Livermore National Laboratory, Macromolecular Crystallography, Biology and Biotechnology Research Program, University of California, Livermore, California 94551, USA.
authors.forename: Heike I
authors.initials: HI
authors.lastname: Krupka
authors.forename: Brent W
authors.initials: BW
authors.lastname: Segelke
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ulrich
authors.forename: Sabine
authors.initials: S
authors.lastname: Ringhofer
authors.forename: Mark
authors.initials: M
authors.lastname: Knapp
authors.forename: Bernhard
authors.initials: B
authors.lastname: Rupp
mesh_terms: D019943:Amino Acid Substitution; D002460:Cell Line; D004768:Enterotoxins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D005802:Genes, MHC Class II; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017385:Sequence Homology; D013209:Staphylococcal Vaccines; D013329:Structure-Activity Relationship; D018089:Superantigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
chemical_list: D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D013209:Staphylococcal Vaccines; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal