7n4x

Structure of human NPC1L1 mutant-W347R

spinqualitylabelsall models 7n4x, resolution 3.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.33Å Ligands: CLR, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption.,Long T, Liu Y, Qin Y, DeBose-Boyd RA, Li X Sci Adv. 2021 Aug 18;7(34). pii: 7/34/eabh3997. doi: 10.1126/sciadv.abh3997., Print 2021 Aug. PMID:34407950 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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