5y9j
BAFF in complex with belimumabBAFF in complex with belimumab
Structural highlights
Function[TN13B_HUMAN] Cytokine that binds to TNFRSF13B/TACI and TNFRSF17/BCMA. TNFSF13/APRIL binds to the same 2 receptors. Together, they form a 2 ligands -2 receptors pathway involved in the stimulation of B- and T-cell function and the regulation of humoral immunity. A third B-cell specific BAFF-receptor (BAFFR/BR3) promotes the survival of mature B-cells and the B-cell response.[1] Isoform 2 seems to inhibit isoform 1 secretion and bioactivity (By similarity).[2] Publication Abstract from PubMedBAFF, 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. BAFF-neutralizing interaction of belimumab related to its therapeutic efficacy for treating systemic lupus erythematosus.,Shin W, Lee HT, Lim H, Lee SH, Son JY, Lee JU, Yoo KY, Ryu SE, Rhie J, Lee JY, Heo YS Nat Commun. 2018 Mar 23;9(1):1200. doi: 10.1038/s41467-018-03620-2. PMID:29572471[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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