Figure 1

Structure of KPT-251 bound to CRM1. (a) Chemical structure of KPT-251. (b) KPT-251 (violet) binds in the NES-binding groove of CRM1 (pink). Select inhibitor-CRM1 interactions (<4 Å) are shown with dashed lines. (c) The overall structure of KPT-251 bound to the ^ScCRM1(T539C)-^HsRan-^ScRanBP1 complex. A space-filling model of KPT-251 is shown together with CRM1 (pink), Ran (green) and RanBP1 (yellow). (d) Surface representation of the NES-binding groove of CRM1 in the inhibitor-free ^ScCRM1-Ran-RanBP1 complex (3M1I). No ligand is bound in the groove, but superimposed KPT-251 (white) is shown for comparison with panel (e). Helices and select side chains below the surface are shown in cyan. (e) Surface representation of the KPT-251-bound CRM1 groove. (f) Surface representations of the ^PKINES-bound CRM1 groove (3NBY). The NES in the structure is removed. No inhibitor is bound in this groove, but superimposed KPT-251 (white) is shown to facilitate comparison with panel (e). (g) Residues 570–605 of CRM1 in the ^ScCRM1-Ran-RanBP1 complex and the KPT-251-^ScCRM1(T539C)-Ran-RanBP1 structures were superimposed (Cα rmsd 0.33 Å) and shown as cartoon representations to compare NES-binding grooves in the two structures. (h) Superposition of the KPT-251- (pink) and ^PKINES-bound (green) grooves. KPT-251 (violet) and the C539 residue (pink) are shown as sticks. The panel on the right is rotated 90° about the vertical axis and helices H12A of the grooves in both structures were removed for a clear side view of the ligands. The ^PKINES and its hydrophobic side chains are bright green.