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TitleStructural basis for itraconazole-mediated NPC1 inhibition.
Journal, issue, pagesNat Commun, Vol. 11, Issue 1, Page 152, Year 2020
Publish dateJan 9, 2020
AuthorsTao Long / Xiaofeng Qi / Abdirahman Hassan / Qiren Liang / Jef K De Brabander / Xiaochun Li /
PubMed AbstractNiemann-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 ...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.
External linksNat Commun / PubMed:31919352 / PubMed Central
MethodsEM (single particle)
Resolution4.02 Å
Structure data

20834

6uox

EMDB-20834, PDB-6uox:
Structure of itraconazole-bound NPC1
Method: EM (single particle) / Resolution: 4.02 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-QDG:
4-(3-bromo-4-{4-[4-({(2R,4S)-2-(2,4-dichlorophenyl)-2-[(1H-1,2,4-triazol-1-yl)methyl]-1,3-dioxolan-4-yl}methoxy)phenyl]piperazin-1-yl}phenyl)-2-[(2S)-butan-2-yl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Niemann-Pick C disease / cholesterol transport / sterol-sensing domain

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