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-Structure paper
タイトル | Cryo-EM structures of NPC1L1 reveal mechanisms of cholesterol transport and ezetimibe inhibition. |
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ジャーナル・号・ページ | Sci Adv, Vol. 6, Issue 25, Page eabb1989, Year 2020 |
掲載日 | 2020年6月19日 |
![]() | Ching-Shin Huang / Xinchao Yu / Preston Fordstrom / Kaylee Choi / Ben C Chung / Soung-Hun Roh / Wah Chiu / Mingyue Zhou / Xiaoshan Min / Zhulun Wang / ![]() |
PubMed 要旨 | The intestinal absorption of cholesterol is mediated by a multipass membrane protein, Niemann-Pick C1-Like 1 (NPC1L1), the molecular target of a cholesterol lowering therapy ezetimibe. While ...The intestinal absorption of cholesterol is mediated by a multipass membrane protein, Niemann-Pick C1-Like 1 (NPC1L1), the molecular target of a cholesterol lowering therapy ezetimibe. While ezetimibe gained Food and Drug Administration approval in 2002, its mechanism of action has remained unclear. Here, we present two cryo-electron microscopy structures of NPC1L1, one in its apo form and the other complexed with ezetimibe. The apo form represents an open state in which the N-terminal domain (NTD) interacts loosely with the rest of NPC1L1, leaving the NTD central cavity accessible for cholesterol loading. The ezetimibe-bound form signifies a closed state in which the NTD rotates ~60°, creating a continuous tunnel enabling cholesterol movement into the plasma membrane. Ezetimibe blocks cholesterol transport by occluding the tunnel instead of competing with cholesterol binding. These findings provide insight into the molecular mechanisms of NPC1L1-mediated cholesterol transport and ezetimibe inhibition, paving the way for more effective therapeutic development. |
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手法 | EM (単粒子) |
解像度 | 3.5 - 3.7 Å |
構造データ | EMDB-21035, PDB-6v3f: EMDB-21037, PDB-6v3h: |
化合物 | ![]() ChemComp-NAG: ![]() ChemComp-CLR: ![]() ChemComp-Y01: ![]() ChemComp-QO1: |
由来 |
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![]() | LIPID TRANSPORT / Cholesterol / Transporter / Tunnel / Sterol / Intestine / Ezetimibe / Sterol-Sensing Domain / LIPID TRANSPORT/INHIBITOR / Inhibitor / LIPID TRANSPORT-INHIBITOR complex |