Person:

Yu, Yamei

The lymphocyte homing receptor integrin (\alpha_4 \beta_7) is unusual for its ability to mediate both rolling and firm adhesion. (\alpha_4 \beta_1) and (\alpha_4 \beta_7) are targeted by therapeutics approved for multiple sclerosis and Crohn’s disease. Here, we show by electron microscopy and crystallography how two therapeutic Fabs, a small molecule (RO0505376), and mucosal adhesion molecule-1 (MAdCAM-1) bind α4β7. A long binding groove at the (\alpha_4 -\beta_7)interface for immunoglobulin superfamily domains differs in shape from integrin pockets that bind Arg-Gly-Asp motifs. RO0505376 mimics an Ile/Leu-Asp motif in (\alpha_4) ligands, and orients differently from Arg-Gly-Asp mimics. A novel auxiliary residue at the metal ion–dependent adhesion site in (\alpha_4 \beta_7) is essential for binding to MAdCAM-1 in (Mg^{2+}) yet swings away when RO0505376 binds. A novel intermediate conformation of the (\alpha_4 \beta_7) headpiece binds MAdCAM-1 and supports rolling adhesion. Lack of induction of the open headpiece conformation by ligand binding enables rolling adhesion to persist until integrin activation is signaled.