Structural basis for itraconazole-mediated NPC1 inhibition

Tao Long, Xiaofeng Qi, Abdirahman Hassan, Qiren Liang, Jef K. De Brabander and Xiaochun Li ()
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Tao Long: University of Texas Southwestern Medical Center
Xiaofeng Qi: University of Texas Southwestern Medical Center
Abdirahman Hassan: University of Texas Southwestern Medical Center
Qiren Liang: University of Texas Southwestern Medical Center
Jef K. De Brabander: University of Texas Southwestern Medical Center
Xiaochun Li: University of Texas Southwestern Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Niemann-Pick C1 (NPC1), a lysosomal protein of 13 transmembrane helices (TMs) and three lumenal domains, exports low-density-lipoprotein (LDL)-derived cholesterol from lysosomes. TMs 3–7 of NPC1 comprise the Sterol-Sensing Domain (SSD). Previous studies suggest that mutation of the NPC1-SSD or the addition of the anti-fungal drug itraconazole abolishes NPC1 activity in cells. However, the itraconazole binding site and the mechanism of NPC1-mediated cholesterol transport remain unknown. Here, we report a cryo-EM structure of human NPC1 bound to itraconazole, which reveals how this binding site in the center of NPC1 blocks a putative lumenal tunnel linked to the SSD. Functional assays confirm that blocking this tunnel abolishes NPC1-mediated cholesterol egress. Intriguingly, the palmitate anchor of Hedgehog occupies a similar site in the homologous tunnel of Patched, suggesting a conserved mechanism for sterol transport in this family of proteins and establishing a central function of their SSDs.

Date: 2020
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DOI: 10.1038/s41467-019-13917-5

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