6UOX

Structure of itraconazole-bound NPC1

Summary for 6UOX

• Entry DOI: 10.2210/pdb6uox/pdb
• EMDB information: 20834
• Descriptor: NPC intracellular cholesterol transporter 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: niemann-pick c disease, cholesterol transport, sterol-sensing domain, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 146880.15

Authors

Long, T.,Li, X. (deposition date: 2019-10-15, release date: 2020-01-15, Last modification date: 2024-11-13)

Primary citation

Long, T.,Qi, X.,Hassan, A.,Liang, Q.,De Brabander, J.K.,Li, X.
Structural basis for itraconazole-mediated NPC1 inhibition.
Nat Commun, 11:152-152, 2020

PubMed 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.

PubMed: 31919352
DOI: 10.1038/s41467-019-13917-5

Experimental method

ELECTRON MICROSCOPY (4.02 Å)