Structure basis for the modulation of CXC chemokine receptor 3 by antagonist AMG487
Haizhan Jiao, Bin Pang, Ying‐Chih Chiang, Qiang Chen, Qi Pan, Ruobing Ren, Hongli Hu
Abstract
CXC chemokine receptor 3 (CXCR3) and three interferon-induced CXC chemokines, specifically CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-TAC), are strongly associated with the migration of CD4 + Th1 cells and CD8 + cytotoxic T lymphocytes in immune responses 1 , 2 . The physiological and pathological functions of CXCR3 have been studied in infection, cancer, autoimmune diseases, and transplant rejection 2 , 3 , 4 , 5 . Only one CXCR3 antagonist, AMG487, has been evaluated in clinical trials for psoriasis and rheumatoid arthritis. AMG487 is a quinazolinone derivative that could prevent the binding of CXCL10 and CXCL11 to CXCR3 with high selectivity 6 . To date, the mechanism of the antagonism of AMG487 remains unclear. Here we determined the structure of CXCR3 complexed with AMG487 and the structure of the CXCR3–DNG i complex activated by CXCL10. The molecular mechanism of CXCR3 inhibition by AMG487 is elucidated, and we believe that our study will provide insightful perspectives for developing CXCR3-targeting antagonists.