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6e7z
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==cryo-EM structure of human TRPML1 with ML-SA1 and PI35P2== | |
| + | <SX load='6e7z' size='340' side='right' viewer='molstar' caption='[[6e7z]], [[Resolution|resolution]] 3.73Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6e7z]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E7Z OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6E7Z FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AQV:2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione'>AQV</scene>, <scene name='pdbligand=HZ7:(1R,2S,3S,4R,5S,6R)-5-{[(R)-[(2R)-2,3-bis{[(1S)-1-hydroxyoctyl]oxy}propoxy](hydroxy)phosphoryl]oxy}-2,4,6-trihydroxycyclohexane-1,3-diyl+bis[dihydrogen+(phosphate)]'>HZ7</scene></td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MCOLN1, ML4, MSTP080 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6e7z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e7z OCA], [http://pdbe.org/6e7z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e7z RCSB], [http://www.ebi.ac.uk/pdbsum/6e7z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e7z ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/MCLN1_HUMAN MCLN1_HUMAN]] Mucolipidosis type 4. The disease is caused by mutations affecting the gene represented in this entry. | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/MCLN1_HUMAN MCLN1_HUMAN]] Cation channel probably playing a role in the endocytic pathway and in the control of membrane trafficking of proteins and lipids. Could play a major role in Ca(2+) transport regulating lysosomal exocytosis.<ref>PMID:12459486</ref> <ref>PMID:14749347</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P2, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P2 and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P2, PtdIns(4,5)P2, or ML-SA1 and PtdIns(3,5)P2, revealing a unique lipid-binding site. PtdIns(3,5)P2 and PtdIns(4,5)P2 bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P2 induces Y355 to form a pi-cation interaction with R403, moving the S4-S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels. | ||
| - | + | Structural basis for PtdInsP2-mediated human TRPML1 regulation.,Fine M, Schmiege P, Li X Nat Commun. 2018 Oct 10;9(1):4192. doi: 10.1038/s41467-018-06493-7. PMID:30305615<ref>PMID:30305615</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 6e7z" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </SX> | ||
| + | [[Category: Human]] | ||
| + | [[Category: Large Structures]] | ||
[[Category: Li, X]] | [[Category: Li, X]] | ||
| + | [[Category: Schmiege, P]] | ||
| + | [[Category: Human trpml1]] | ||
| + | [[Category: Membrane protein]] | ||
Current revision
cryo-EM structure of human TRPML1 with ML-SA1 and PI35P2
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