+Open data
-Basic information
Entry | Database: PDB / ID: 7mgl | ||||||
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Title | Structure of human TRPML1 with ML-SI3 | ||||||
Components | Mucolipin-1 | ||||||
Keywords | MEMBRANE PROTEIN / TRPML / Calcium / ML-SI3 | ||||||
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 | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å | ||||||
Authors | Schmiege, P. / Li, X. | ||||||
Citation | Journal: Structure / Year: 2021 Title: Atomic insights into ML-SI3 mediated human TRPML1 inhibition. Authors: Philip Schmiege / Michael Fine / Xiaochun Li / Abstract: Transient receptor potential mucolipin 1 (TRPML1) regulates lysosomal calcium signaling, lipid trafficking, and autophagy-related processes. This channel is regulated by phosphoinositides and the low ...Transient receptor potential mucolipin 1 (TRPML1) regulates lysosomal calcium signaling, lipid trafficking, and autophagy-related processes. This channel is regulated by phosphoinositides and the low pH environment of the lysosome, maintaining calcium levels essential for proper lysosomal function. Recently, several small molecules specifically targeting the TRPML family have been demonstrated to modulate channel activity. One of these, a synthetic antagonist ML-SI3, can prevent lysosomal calcium efflux and has been reported to block downstream TRPML1-mediated induction of autophagy. Here, we report a cryo-electron microscopy structure of human TRPML1 with ML-SI3 at 2.9-Å resolution. ML-SI3 binds to the hydrophobic cavity created by S5, S6, and PH1, the same cavity where the synthetic agonist ML-SA1 binds. Electrophysiological characterizations show that ML-SI3 can compete with ML-SA1, blocking channel activation yet does not inhibit PI(3,5)P-dependent activation of the channel. Consequently, this work provides molecular insight into how ML-SI3 and native lipids regulate TRPML1 activity. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7mgl.cif.gz | 334.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7mgl.ent.gz | 283.9 KB | Display | PDB format |
PDBx/mmJSON format | 7mgl.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7mgl_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 7mgl_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 7mgl_validation.xml.gz | 59.2 KB | Display | |
Data in CIF | 7mgl_validation.cif.gz | 83.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/mg/7mgl ftp://data.pdbj.org/pub/pdb/validation_reports/mg/7mgl | HTTPS FTP |
-Related structure data
Related structure data | 23828MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 65084.996 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MCOLN1, ML4, MSTP080 / Production host: Homo sapiens (human) / References: UniProt: Q9GZU1 #2: Chemical | ChemComp-ZB4 / #3: Chemical | ChemComp-3PE / Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: TRPML1 complex with ML-SI3 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 4.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: DARK FIELD |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.16_3549: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 508465 / Symmetry type: POINT | ||||||||||||||||||||||||
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