Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
PLoS One. 2011 Apr 15;6(4):e18722. doi: 10.1371/journal.pone.0018722.
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.
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.
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.
NPC1L1 是降脂药物依折麦布的分子靶标，介导胆固醇的肠道吸收。NPC1L1 的抑制或缺失会减少肠道胆固醇吸收，导致血浆胆固醇水平降低。
本文呈现了 NPC1L1 无胆固醇状态下的 N 端结构域（NTD）的 2.8Å 晶体结构。该结构与生化数据相结合，揭示了 NPC1L1 胆固醇选择性的机制。与 NPC1（NTD）的无胆固醇和结合胆固醇结构的比较表明，NPC1L1（NTD）处于封闭构象，固醇结合口袋与溶剂隔离。
NPC1L1（NTD）的结构揭示了固醇结合口袋入口周围存在一定程度的灵活性，表明其门控机制依赖于固醇结合口袋入口周围的多个运动。
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