Figure 1
Figure 1. Structure of SINEs bound to XPO1. (A) Chemical structure of KPT-185 and KPT-251 with their heavy atoms numbered. KPT-185 (MW of 355.3) contains a phenyl triazole attached to an isopropyl acrylate via triazole nitrogen. It has good physical properties with cLog P and polar surface area (PSA) of 3.8 and 63.5, respectively. KPT-251 (MW of 375.3), contains a phenyl triazole attached to an oxadiazole ring via a double bond. KPT-251 is a relatively polar compound, and exhibits good physical properties with cLog P and polar surface area (PSA) of 2.5 and 61.9, respectively. (B) The overall structure of the KPT185-ScXPO1*-HsRan-ScRanBP1 complex. A space-filling model of KPT-185 is shown along with XPO1 (pink), Ran (green), and RanBP1 (yellow). (C) The NES-binding groove is located between HEAT repeats H11 and H12, and lined with residues from helices H11A, H11B, H12A and H12B KPT-185 (orange) binds in the NES-binding groove of XPO1 (pink). KPT-185 is oriented with its trifluoromethyl methoxy phenyl group pointing toward the bottom of the XPO1 groove (C-terminal ends of helices H11A and H12A), whereas its isopropyl ester group heads in the opposite direction toward the top of the groove. The activated alkene of KPT-185 is conjugated to the Cys539 sidechain of ScXPO1* through Michael reaction. The methoxy substituent of KPT-185 is partially exposed to solvent but also participates in hydrophobic interactions with the Phe572, Thr575 and Val576 sidechains, which are all located on helix H12A of XPO1. The phenyl ring of KPT-185 is sandwiched between 2 hydrophobic layers. One layer consists of Leu536 and Ile555 sidechains and the other layer consists of the Phe 583 sidechain and the aliphatic portion of the Lys579 sidechain. The triazole ring of KPT-185 is surrounded by hydrophobic XPO1 sidechains sandwiched by Leu536, Cys539 and Ile555 sidechains on one side and the edge of the Phe583 ring on the other. The nitrogen atoms in the triazole ring of KPT-185 make no polar contacts but participate in van der Waals contacts with XPO1 residues. Similarly, polar moieties in the isopropyl ester of KPT-185 make no polar contact with XPO1. The isopropyl ester binds near the top of the XPO1 groove lying close to the floor of the groove with its carbonyl pointing toward solvent and its isopropyl group interacting with the Phe583 and Glu586 sidechains that are located at the C-terminal end of helix H12A. Select inhibitor-XPO1 interactions (< 4Å) are shown with dashed lines. (D-E) Conformational changes in the NES-binding groove of XPO1. (D) The NES-binding groove of XPO1 in the inhibitor-free ScXPO1-Ran-RanBP1 complex (3M1l) is shown as surface representation. The helices and select side chains below the surface are shown in cyan. No ligand is bound in the groove of this XPO1 complex but KPT-185 (placed from superposition of XPO1 residues 570-605 of the ScXPO1-Ran-RanBP1 and the KPT-185-ScXPO1*-Ran-RanBP1 structures) is shown as a reference to facilitate comparison with (E). (E) The NES-binding groove of XPO1 in the KPT-185-ScXPO1*-Ran-RanBP1 complex is shown as surface representation. The helices and select sidechains below the surface are shown in pink and KPT-185 is shown as a stick figure in orange.

Structure of SINEs bound to XPO1. (A) Chemical structure of KPT-185 and KPT-251 with their heavy atoms numbered. KPT-185 (MW of 355.3) contains a phenyl triazole attached to an isopropyl acrylate via triazole nitrogen. It has good physical properties with cLog P and polar surface area (PSA) of 3.8 and 63.5, respectively. KPT-251 (MW of 375.3), contains a phenyl triazole attached to an oxadiazole ring via a double bond. KPT-251 is a relatively polar compound, and exhibits good physical properties with cLog P and polar surface area (PSA) of 2.5 and 61.9, respectively. (B) The overall structure of the KPT185-ScXPO1*-HsRan-ScRanBP1 complex. A space-filling model of KPT-185 is shown along with XPO1 (pink), Ran (green), and RanBP1 (yellow). (C) The NES-binding groove is located between HEAT repeats H11 and H12, and lined with residues from helices H11A, H11B, H12A and H12B KPT-185 (orange) binds in the NES-binding groove of XPO1 (pink). KPT-185 is oriented with its trifluoromethyl methoxy phenyl group pointing toward the bottom of the XPO1 groove (C-terminal ends of helices H11A and H12A), whereas its isopropyl ester group heads in the opposite direction toward the top of the groove. The activated alkene of KPT-185 is conjugated to the Cys539 sidechain of ScXPO1* through Michael reaction. The methoxy substituent of KPT-185 is partially exposed to solvent but also participates in hydrophobic interactions with the Phe572, Thr575 and Val576 sidechains, which are all located on helix H12A of XPO1. The phenyl ring of KPT-185 is sandwiched between 2 hydrophobic layers. One layer consists of Leu536 and Ile555 sidechains and the other layer consists of the Phe 583 sidechain and the aliphatic portion of the Lys579 sidechain. The triazole ring of KPT-185 is surrounded by hydrophobic XPO1 sidechains sandwiched by Leu536, Cys539 and Ile555 sidechains on one side and the edge of the Phe583 ring on the other. The nitrogen atoms in the triazole ring of KPT-185 make no polar contacts but participate in van der Waals contacts with XPO1 residues. Similarly, polar moieties in the isopropyl ester of KPT-185 make no polar contact with XPO1. The isopropyl ester binds near the top of the XPO1 groove lying close to the floor of the groove with its carbonyl pointing toward solvent and its isopropyl group interacting with the Phe583 and Glu586 sidechains that are located at the C-terminal end of helix H12A. Select inhibitor-XPO1 interactions (< 4Å) are shown with dashed lines. (D-E) Conformational changes in the NES-binding groove of XPO1. (D) The NES-binding groove of XPO1 in the inhibitor-free ScXPO1-Ran-RanBP1 complex (3M1l) is shown as surface representation. The helices and select side chains below the surface are shown in cyan. No ligand is bound in the groove of this XPO1 complex but KPT-185 (placed from superposition of XPO1 residues 570-605 of the ScXPO1-Ran-RanBP1 and the KPT-185-ScXPO1*-Ran-RanBP1 structures) is shown as a reference to facilitate comparison with (E). (E) The NES-binding groove of XPO1 in the KPT-185-ScXPO1*-Ran-RanBP1 complex is shown as surface representation. The helices and select sidechains below the surface are shown in pink and KPT-185 is shown as a stick figure in orange.

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