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Structural basis for itraconazole-mediated NPC1 inhibition

Author

Listed:
  • 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
    University of Texas Southwestern Medical Center)

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.

Suggested Citation

  • Tao Long & Xiaofeng Qi & Abdirahman Hassan & Qiren Liang & Jef K. De Brabander & Xiaochun Li, 2020. "Structural basis for itraconazole-mediated NPC1 inhibition," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13917-5
    DOI: 10.1038/s41467-019-13917-5
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    Cited by:

    1. Wanqiu Li & Linlin Wang & Bradley M. Wierbowski & Mo Lu & Feitong Dong & Wenchen Liu & Sisi Li & Peiyi Wang & Adrian Salic & Xin Gong, 2021. "Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Hongwen Chen & Xiaofeng Qi & Rebecca A. Faulkner & Marc M. Schumacher & Linda M. Donnelly & Russell A. DeBose-Boyd & Xiaochun Li, 2022. "Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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