Abstract
Staphylococcal enterotoxin A (SEA) cross-links two class II major histocompatibility complex (MHC) molecules and forms a multimeric assembly with T-cell receptors (TcRs). The X-ray crystal structure of SEA has been solved, yet details describing molecular recognition and association remain unclear. We present a structural model for the interactions of SEA with cell-surface proteins. Molecular docking calculations predicting SEA association with the class II MHC molecule HLA-DR1 were performed by using a rigid-body docking method. Docked orientations were evaluated by a Poisson–Boltzmann model for the electrostatic free energy of binding and the hydrophobic effect calculated from molecular surface areas. We found that the best-scoring SEA conformers for the DR1α interface display a binding mode similar to that determined crystallographically for staphylococcal enterotoxin B bound to HLA-DR1. For the zinc-binding site of SEA, docking DR1β yielded several orientations exhibiting tetrahedral-like coordination geometries. Combining the two interfaces, tetramers were modeled by docking an αβ TcR with trimolecular complexes DR1β–SEA–DR1α and SEA–βDR1α–SEA. Our results indicate that the complex DR1β–SEA–DR1α provides a more favorable assembly for the engagement of TcRs, forming SEA molecular contacts that are in accord with reported mutagenesis studies. In contrast, the cooperative association of two SEA molecules on a single DR1 molecule sterically inhibits interactions with TcRs. We suggest that signal transduction stimulated by SEA through large-scale assembly is limited to four or five TcR–(DR1β–SEA–DR1α) tetramers and requires the dimerization of class II MHC molecules, while TcR dimerization is unlikely.
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