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-Structure paper
タイトル | Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake. |
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ジャーナル・号・ページ | Sci Adv, Vol. 7, Issue 29, Year 2021 |
掲載日 | 2021年7月16日 |
著者 | Miaoqing Hu / Fan Yang / Yawen Huang / Xin You / Desheng Liu / Shan Sun / Sen-Fang Sui / |
PubMed 要旨 | Niemann-Pick C1-like 1 (NPC1L1) protein plays a central role in the intestinal cholesterol absorption and is the target of a drug, ezetimibe, which inhibits NPC1L1 to reduce cholesterol absorption. ...Niemann-Pick C1-like 1 (NPC1L1) protein plays a central role in the intestinal cholesterol absorption and is the target of a drug, ezetimibe, which inhibits NPC1L1 to reduce cholesterol absorption. Here, we present cryo-electron microscopy structures of human NPC1L1 in apo state, cholesterol-enriched state, and ezetimibe-bound state to reveal molecular details of NPC1L1-mediated cholesterol uptake and ezetimibe inhibition. Comparison of these structures reveals that the sterol-sensing domain (SSD) could respond to the cholesterol level alteration by binding different number of cholesterol molecules. Upon increasing cholesterol level, SSD binds more cholesterol molecules, which, in turn, triggers the formation of a stable structural cluster in SSD, while binding of ezetimibe causes the deformation of the SSD and destroys the structural cluster, leading to the inhibition of NPC1L1 function. These results provide insights into mechanisms of NPC1L1 function and ezetimibe action and are of great significance for the development of new cholesterol absorption inhibitors. |
リンク | Sci Adv / PubMed:34272236 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.69 - 3.58 Å |
構造データ | EMDB-30662, PDB-7df8: EMDB-30666, PDB-7dfw: EMDB-30667: EMDB-30668, PDB-7dfz: |
化合物 | ChemComp-NAG: ChemComp-LMT: ChemComp-CLR: ChemComp-P5S: ChemComp-H56: |
由来 |
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キーワード | MEMBRANE PROTEIN / cholesterol / STRUCTURAL PROTEIN / STRUCTURAL PROTEIN/INHIBITOR / Ezetimibe / STRUCTURAL PROTEIN-INHIBITOR Complex |