fig2

Figure 2. Structural features of XPO1 related to its nuclear export function, its role in cancer and its potential as a therapeutic target. A: Schematic representation of XPO1 protein illustrating its general ring-shaped conformation, and showing the three structural motifs that are crucial for its function as a nuclear export receptor: the NES-binding groove, the H9 loop and the C-terminal extension; B: detailed views of the NES-binding groove on the molecular surface of XPO1. The UCSF Chimera package^[206] and XPO1 structure 3GJX^[207] were used to generate the images. The left panel shows the empty groove, the middle panel shows a “leucine-rich” NES peptide (pink) bound to the groove. The right panel shows residues E571 and C528 highlighted in blue. E571 is a mutational hotspot in several hematological malignancies. C528 is the residue targeted by XPO1-inhibiting drugs, such as LMB or Selinexor. These compounds attach covalently to C528 and physically occupy the groove, blocking NES binding. NES: nuclear export signal; LMB: leptomycin B