7N4U

Structure of human NPC1L1

Summary for 7N4U

• Entry DOI: 10.2210/pdb7n4u/pdb
• EMDB information: 24178
• Descriptor: Isoform 2 of NPC1-like intracellular cholesterol transporter 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: transporter, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 300052.31

Authors

Li, X.,Long, T. (deposition date: 2021-06-04, release date: 2021-09-01, Last modification date: 2024-11-13)

Primary citation

Long, T.,Liu, Y.,Qin, Y.,DeBose-Boyd, R.A.,Li, X.
Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption.
Sci Adv, 7:-, 2021

PubMed Abstract: Polytopic Niemann-Pick C1-like 1 (NPC1L1) plays a major role in intestinal absorption of biliary cholesterol, vitamin E (VE), and vitamin K (VK). The drug ezetimibe inhibits NPC1L1-mediated absorption of cholesterol, lowering of circulating levels of low-density lipoprotein cholesterol. Here, we report cryo-electron microscopy structures of human NPC1L1 (hNPC1L1) bound to either cholesterol or a lipid resembling VE. These findings, together with functional assays, reveal that the same intramolecular channel in hNPC1L1 mediates transport of VE and cholesterol. hNPC1L1 exists primarily as a homodimer; dimerization is mediated by aromatic residues within a region of transmembrane helix 2 that exhibits a horizonal orientation in the membrane. Mutation of tryptophan-347 lies in this region disrupts dimerization and the resultant monomeric NPC1L1 exhibits reduced efficiency of cholesterol uptake. These findings identify the oligomeric state of hNPC1L1 as a target for therapies that inhibit uptake of dietary cholesterol and reduce the incidence of cardiovascular disease.

PubMed: 34407950
DOI: 10.1126/sciadv.abh3997

Experimental method

ELECTRON MICROSCOPY (3.34 Å)