title: The structure of the NPC1L1 N-terminal domain in a closed conformation.
abstract: BACKGROUND
  NPC1L1 is the molecular target of the cholesterol lowering drug Ezetimibe and mediates the intestinal absorption of cholesterol. Inhibition or deletion of NPC1L1 reduces intestinal cholesterol absorption, resulting in reduction of plasma cholesterol levels.
  
  
  RESULTS
  Here we present the 2.8 Å crystal structure of the N-terminal domain (NTD) of NPC1L1 in the absence of cholesterol. The structure, combined with biochemical data, reveals the mechanism of cholesterol selectivity of NPC1L1. Comparison to the cholesterol free and bound structures of NPC1(NTD) reveals that NPC1L1(NTD) is in a closed conformation and the sterol binding pocket is occluded from solvent.
  
  
  CONCLUSIONS
  The structure of NPC1L1(NTD) reveals a degree of flexibility surrounding the entrance to the sterol binding pocket, suggesting a gating mechanism that relies on multiple movements around the entrance to the sterol binding pocket.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. hyockjoo.kwon@gmail.com
authors.forename: Hyock Joo
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Maya
authors.initials: M
authors.lastname: Palnitkar
authors.forename: Johann
authors.initials: J
authors.lastname: Deisenhofer
mesh_terms: D000595:Amino Acid Sequence; D002784:Cholesterol / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D002784:Cholesterol