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| | <StructureSection load='3qnt' size='340' side='right'caption='[[3qnt]], [[Resolution|resolution]] 2.83Å' scene=''> | | <StructureSection load='3qnt' size='340' side='right'caption='[[3qnt]], [[Resolution|resolution]] 2.83Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3qnt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QNT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QNT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3qnt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QNT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QNT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.83Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NPC1L1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3qnt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qnt OCA], [https://pdbe.org/3qnt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qnt RCSB], [https://www.ebi.ac.uk/pdbsum/3qnt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qnt ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3qnt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qnt OCA], [https://pdbe.org/3qnt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qnt RCSB], [https://www.ebi.ac.uk/pdbsum/3qnt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qnt ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/NPCL1_HUMAN NPCL1_HUMAN]] Plays a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorbtion. Lack of activity leads to multiple lipid transport defects. The protein may have a function in the transport of multiple lipids and their homeostasis, and may play a critical role in regulating lipid metabolism. Acts as a negative regulator of NPC2 and down-regulates its expression and secretion by inhibiting its maturation and accelerating its degradation.<ref>PMID:15928087</ref> <ref>PMID:22095670</ref>
| + | [https://www.uniprot.org/uniprot/NPCL1_HUMAN NPCL1_HUMAN] Plays a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorbtion. Lack of activity leads to multiple lipid transport defects. The protein may have a function in the transport of multiple lipids and their homeostasis, and may play a critical role in regulating lipid metabolism. Acts as a negative regulator of NPC2 and down-regulates its expression and secretion by inhibiting its maturation and accelerating its degradation.<ref>PMID:15928087</ref> <ref>PMID:22095670</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Kwon, H J]] | + | [[Category: Kwon HJ]] |
| - | [[Category: Cholesterol transport protein]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Function
NPCL1_HUMAN Plays a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorbtion. Lack of activity leads to multiple lipid transport defects. The protein may have a function in the transport of multiple lipids and their homeostasis, and may play a critical role in regulating lipid metabolism. Acts as a negative regulator of NPC2 and down-regulates its expression and secretion by inhibiting its maturation and accelerating its degradation.[1] [2]
Publication Abstract from PubMed
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. PRINCIPAL FINDINGS: Here we present the 2.8 A 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. CONCLUSION: 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.
The Structure of the NPC1L1 N-Terminal Domain in a Closed Conformation.,Kwon HJ, Palnitkar M, Deisenhofer J PLoS One. 2011 Apr 15;6(4):e18722. PMID:21525977[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, Crona JH, Davis HR Jr, Dean DC, Detmers PA, Graziano MP, Hughes M, Macintyre DE, Ogawa A, O'neill KA, Iyer SP, Shevell DE, Smith MM, Tang YS, Makarewicz AM, Ujjainwalla F, Altmann SW, Chapman KT, Thornberry NA. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8132-7. Epub 2005 May 31. PMID:15928087 doi:10.1073/pnas.0500269102
- ↑ Yamanashi Y, Takada T, Shoda J, Suzuki H. Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein. Hepatology. 2012 Mar;55(3):953-64. doi: 10.1002/hep.24772. Epub 2012 Jan 30. PMID:22095670 doi:10.1002/hep.24772
- ↑ Kwon HJ, Palnitkar M, Deisenhofer J. The Structure of the NPC1L1 N-Terminal Domain in a Closed Conformation. PLoS One. 2011 Apr 15;6(4):e18722. PMID:21525977 doi:10.1371/journal.pone.0018722
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