BAFF, a member of the TNF superfamily, has been recognized as a good target for 
autoimmune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved 
by the FDA for use in treating systemic lupus erythematosus. However, the 
molecular basis of BAFF neutralization by belimumab remains unclear. Here our 
crystal structure of the BAFF-belimumab Fab complex shows the precise epitope 
and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the 
therapeutic activity of belimumab involves not only antagonizing the 
BAFF-receptor interaction, but also disrupting the formation of the more active 
BAFF 60-mer to favor the induction of the less active BAFF trimer through 
interaction with the flap region of BAFF. In addition, the belimumab HCDR3 loop 
mimics the DxL(V/L) motif of BAFF receptors, thereby binding to BAFF in a 
similar manner as endogenous BAFF receptors. Our data thus provides insights for 
the design of new drugs targeting BAFF for the treatment of autoimmune diseases.