Structural basis for abrogated binding between staphylococcal enterotoxin A superantigen vaccine and MHC-IIalpha.
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.
Krupka
Heike I
HI
Lawrence Livermore National Laboratory, Macromolecular Crystallography, Biology and Biotechnology Research Program, University of California, Livermore, California 94551, USA.
Segelke
Brent W
BW
Ulrich
Robert G
RG
Ringhofer
Sabine
S
Knapp
Mark
M
Rupp
Bernhard
B
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*
D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D013209:Staphylococcal Vaccines; D018089:Superantigens; C026066:enterotoxin A, Staphylococcal