7azn
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of mouse AsterC (GramD1c) with a new cholesterol-derived compound== | |
| + | <StructureSection load='7azn' size='340' side='right'caption='[[7azn]], [[Resolution|resolution]] 2.09Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[7azn]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AZN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AZN FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.09Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EOH:ETHANOL'>EOH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=YK8:20alpha-hydroxy-20-(5-methylhexyl)cholesterol'>YK8</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=7azn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7azn OCA], [https://pdbe.org/7azn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7azn RCSB], [https://www.ebi.ac.uk/pdbsum/7azn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7azn ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/ASTRC_MOUSE ASTRC_MOUSE] Cholesterol transporter that mediates non-vesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER) (PubMed:30220461). Contains unique domains for binding cholesterol and the PM, thereby serving as a molecular bridge for the transfer of cholesterol from the PM to the ER (PubMed:30220461). Plays a crucial role in cholesterol homeostasis and has the unique ability to localize to the PM based on the level of membrane cholesterol (PubMed:30220461). In lipid-poor conditions localizes to the ER membrane and in response to excess cholesterol in the PM is recruited to the endoplasmic reticulum-plasma membrane contact sites (EPCS) which is mediated by the GRAM domain (PubMed:30220461). At the EPCS, the sterol-binding VASt/ASTER domain binds to the cholesterol in the PM and facilitates its transfer from the PM to ER (PubMed:30220461).<ref>PMID:30220461</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The Aster proteins (encoded by the Gramd1a-c genes) contain a ligand-binding fold structurally similar to a START domain and mediate nonvesicular plasma membrane (PM) to endoplasmic reticulum (ER) cholesterol transport. In an effort to develop small molecule modulators of Asters, we identified 20alpha-hydroxycholesterol (HC) and U18666A as lead compounds. Unfortunately, both 20alpha-HC and U18666A target other sterol homeostatic proteins, limiting their utility. 20alpha-HC inhibits sterol regulatory element-binding protein 2 (SREBP2) processing, and U18666A is an inhibitor of the vesicular trafficking protein Niemann-Pick C1 (NPC1). To develop potent and selective Aster inhibitors, we synthesized a series of compounds by modifying 20alpha-HC and U18666A. Among these, AI (Aster inhibitor)-1l, which has a longer side chain than 20alpha-HC, selectively bound to Aster-C. The crystal structure of Aster-C in complex with AI-1l suggests that sequence and flexibility differences in the loop that gates the binding cavity may account for the ligand specificity for Aster C. We further identified the U18666A analog AI-3d as a potent inhibitor of all three Aster proteins. AI-3d blocks the ability of Asters to bind and transfer cholesterol in vitro and in cells. Importantly, AI-3d also inhibits the movement of low-density lipoprotein (LDL) cholesterol to the ER, although AI-3d does not block NPC1. This finding positions the nonvesicular Aster pathway downstream of NPC1-dependent vesicular transport in the movement of LDL cholesterol to the ER. Selective Aster inhibitors represent useful chemical tools to distinguish vesicular and nonvesicular sterol transport mechanisms in mammalian cells. | ||
| - | + | Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms.,Xiao X, Kim Y, Romartinez-Alonso B, Sirvydis K, Ory DS, Schwabe JWR, Jung ME, Tontonoz P Proc Natl Acad Sci U S A. 2021 Jan 12;118(2). pii: 2024149118. doi:, 10.1073/pnas.2024149118. PMID:33376205<ref>PMID:33376205</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 7azn" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Mus musculus]] | ||
| + | [[Category: Jung M]] | ||
| + | [[Category: Kim Y]] | ||
| + | [[Category: Romartinez-Alonso B]] | ||
| + | [[Category: Schwabe J]] | ||
| + | [[Category: Sirvydis K]] | ||
| + | [[Category: Tontonoz P]] | ||
| + | [[Category: Xiao X]] | ||
Current revision
Structure of mouse AsterC (GramD1c) with a new cholesterol-derived compound
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Categories: Large Structures | Mus musculus | Jung M | Kim Y | Romartinez-Alonso B | Schwabe J | Sirvydis K | Tontonoz P | Xiao X
