+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-9002 | |||||||||
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Title | cryo-EM structure of human TRPML1 with ML-SA1 and PI35P2 | |||||||||
Map data | primary map | |||||||||
Sample |
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Function / homology | Function and homology information calcium ion export / positive regulation of lysosome organization / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / phagosome maturation / NAADP-sensitive calcium-release channel activity / iron ion transmembrane transporter activity / iron ion transmembrane transport / transferrin transport / Transferrin endocytosis and recycling / cellular response to pH ...calcium ion export / positive regulation of lysosome organization / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / phagosome maturation / NAADP-sensitive calcium-release channel activity / iron ion transmembrane transporter activity / iron ion transmembrane transport / transferrin transport / Transferrin endocytosis and recycling / cellular response to pH / monoatomic anion channel activity / ligand-gated calcium channel activity / TRP channels / sodium channel activity / monoatomic cation transport / phagocytic cup / autophagosome maturation / potassium channel activity / monoatomic cation channel activity / release of sequestered calcium ion into cytosol / cellular response to calcium ion / cell projection / calcium ion transmembrane transport / calcium channel activity / phagocytic vesicle membrane / late endosome / late endosome membrane / protein homotetramerization / adaptive immune response / receptor complex / endosome membrane / lysosome / lysosomal membrane / intracellular membrane-bounded organelle / lipid binding / Golgi apparatus / nucleoplasm / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.73 Å | |||||||||
Authors | Schmiege P / Li X | |||||||||
Citation | Journal: Nat Commun / Year: 2018 Title: Structural basis for PtdInsP-mediated human TRPML1 regulation. Authors: Michael Fine / Philip Schmiege / Xiaochun Li / Abstract: 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 ...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)P), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P, PtdIns(4,5)P, or ML-SA1 and PtdIns(3,5)P, revealing a unique lipid-binding site. PtdIns(3,5)P and PtdIns(4,5)P bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P induces Y355 to form a π-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. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_9002.map.gz | 87.6 MB | EMDB map data format | |
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Header (meta data) | emd-9002-v30.xml emd-9002.xml | 10.5 KB 10.5 KB | Display Display | EMDB header |
Images | emd_9002.png | 65.9 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-9002 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-9002 | HTTPS FTP |
-Validation report
Summary document | emd_9002_validation.pdf.gz | 425.5 KB | Display | EMDB validaton report |
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Full document | emd_9002_full_validation.pdf.gz | 425 KB | Display | |
Data in XML | emd_9002_validation.xml.gz | 6.6 KB | Display | |
Data in CIF | emd_9002_validation.cif.gz | 7.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-9002 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-9002 | HTTPS FTP |
-Related structure data
Related structure data | 6e7zMC 9000C 9001C 6e7pC 6e7yC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_9002.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | primary map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : TRPML1
Entire | Name: TRPML1 |
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Components |
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-Supramolecule #1: TRPML1
Supramolecule | Name: TRPML1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Macromolecule #1: Mucolipin-1
Macromolecule | Name: Mucolipin-1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 65.084996 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MTAPAGPRGS ETERLLTPNP GYGTQAGPSP APPTPPEEED LRRRLKYFFM SPCDKFRAKG RKPCKLMLQV VKILVVTVQL ILFGLSNQL AVTFREENTI AFRHLFLLGY SDGADDTFAA YTREQLYQAI FHAVDQYLAL PDVSLGRYAY VRGGGDPWTN G SGLALCQR ...String: MTAPAGPRGS ETERLLTPNP GYGTQAGPSP APPTPPEEED LRRRLKYFFM SPCDKFRAKG RKPCKLMLQV VKILVVTVQL ILFGLSNQL AVTFREENTI AFRHLFLLGY SDGADDTFAA YTREQLYQAI FHAVDQYLAL PDVSLGRYAY VRGGGDPWTN G SGLALCQR YYHRGHVDPA NDTFDIDPMV VTDCIQVDPP ERPPPPPSDD LTLLESSSSY KNLTLKFHKL VNVTIHFRLK TI NLQSLIN NEIPDCYTFS VLITFDNKAH SGRIPISLET QAHIQECKHP SVFQHGDNSF RLLFDVVVIL TCSLSFLLCA RSL LRGFLL QNEFVGFMWR QRGRVISLWE RLEFVNGWYI LLVTSDVLTI SGTIMKIGIE AKNLASYDVC SILLGTSTLL VWVG VIRYL TFFHNYNILI ATLRVALPSV MRFCCCVAVI YLGYCFCGWI VLGPYHVKFR SLSMVSECLF SLINGDDMFV TFAAM QAQQ GRSSLVWLFS QLYLYSFISL FIYMVLSLFI ALITGAYDTI KHPGGAGAEE SELQAYIAQC QDSPTSGKFR RGSGSA CSL LCCCGRDPSE EHSLLVN |
-Macromolecule #2: (1R,2S,3S,4R,5S,6R)-5-{[(R)-[(2R)-2,3-bis{[(1S)-1-hydroxyoctyl]ox...
Macromolecule | Name: (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)] type: ligand / ID: 2 / Number of copies: 4 / Formula: HZ7 |
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Molecular weight | Theoretical: 750.598 Da |
Chemical component information | ChemComp-HZ7: |
-Macromolecule #3: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]eth...
Macromolecule | Name: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione type: ligand / ID: 3 / Number of copies: 4 / Formula: AQV |
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Molecular weight | Theoretical: 362.422 Da |
Chemical component information | ChemComp-AQV: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 7 mg/mL |
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Buffer | pH: 7 |
Grid | Details: unspecified |
Vitrification | Cryogen name: NITROGEN |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 1.6 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |