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The structure of the NPC1L1 N-terminal domain in a closed conformation

Hyock Joo Kwon1, Maya Palnitkar, Johann Deisenhofer

  • 1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. hyockjoo.kwon@gmail.com

Plos One
|April 29, 2011
PubMed
Abstract

Insights

The Niemann-Pick C1-Like 1 (NPC1L1) protein

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Medicine

Background:

  • NPC1L1 is the molecular target of Ezetimibe, a cholesterol-lowering drug.
  • NPC1L1 mediates intestinal cholesterol absorption, impacting plasma cholesterol levels.
  • Inhibiting NPC1L1 reduces cholesterol absorption and lowers plasma cholesterol.

Purpose of the Study:

  • To elucidate the structural basis of NPC1L1's cholesterol selectivity.
  • To understand the mechanism of cholesterol binding by NPC1L1.

Main Methods:

  • X-ray crystallography to determine the 2.8 Å structure of NPC1L1 N-terminal domain (NTD).
  • Biochemical assays to complement structural data.

Main Results:

  • The crystal structure of NPC1L1 NTD in the absence of cholesterol was determined.
  • NPC1L1 NTD adopts a closed conformation, occluding the sterol binding pocket.
  • Comparison with NPC1 NTD structures reveals differences in cholesterol binding mechanisms.

Conclusions:

  • The NPC1L1 NTD structure suggests a gating mechanism for sterol binding.
  • Flexibility around the sterol binding pocket entrance indicates a dynamic binding process.

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