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- EMDB-25377: Cryo-EM structure of mouse agonist ML-SA1-bound TRPML1 channel at... -

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Basic information

Entry
Database: EMDB / ID: EMD-25377
TitleCryo-EM structure of mouse agonist ML-SA1-bound TRPML1 channel at 2.32 Angstrom resolution
Map data
Sample
  • Complex: Mouse Transient receptor potential-mucolipin 1 apo closed state
    • Protein or peptide: Mucolipin-1MCOLN1
  • Ligand: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione
  • Ligand: SODIUM IONSodium
  • Ligand: water
Function / homology
Function and homology information


Transferrin endocytosis and recycling / positive regulation of lysosome organization / calcium ion export / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / phagosome maturation / NAADP-sensitive calcium-release channel activity / cellular response to pH / ligand-gated calcium channel activity / TRP channels / endosomal transport ...Transferrin endocytosis and recycling / positive regulation of lysosome organization / calcium ion export / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / phagosome maturation / NAADP-sensitive calcium-release channel activity / cellular response to pH / ligand-gated calcium channel activity / TRP channels / endosomal transport / phagocytic cup / intracellular vesicle / autophagosome maturation / monoatomic cation transmembrane transport / localization / release of sequestered calcium ion into cytosol / monoatomic cation channel activity / cellular response to calcium ion / cell projection / calcium ion transmembrane transport / phagocytic vesicle membrane / late endosome / late endosome membrane / protein homotetramerization / adaptive immune response / lysosome / receptor complex / lysosomal membrane / intracellular membrane-bounded organelle / lipid binding / Golgi apparatus / nucleoplasm / membrane / identical protein binding / plasma membrane
Similarity search - Function
: / : / Mucolipin, extracytosolic domain / Mucolipin / Polycystin cation channel, PKD1/PKD2 / Polycystin cation channel
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.32 Å
AuthorsGan N / Han Y / Jiang Y
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM140892
Welch FoundationI-1578 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P and rapamycin.
Authors: Ninghai Gan / Yan Han / Weizhong Zeng / Yan Wang / Jing Xue / Youxing Jiang /
Abstract: Transient receptor potential mucolipin 1 (TRPML1) is a Ca-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are ...Transient receptor potential mucolipin 1 (TRPML1) is a Ca-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are the direct cause of type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease. TRPML1 is a ligand-gated channel that can be activated by phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] as well as some synthetic small-molecule agonists. Recently, rapamycin has also been shown to directly bind and activate TRPML1. Interestingly, both PI(3,5)P and rapamycin have low efficacy in channel activation individually but together they work cooperatively and activate the channel with high potency. To reveal the structural basis underlying the synergistic activation of TRPML1 by PI(3,5)P and rapamycin, we determined the high-resolution cryoelectron microscopy (cryo-EM) structures of the mouse TRPML1 channel in various states, including apo closed, PI(3,5)P-bound closed, and PI(3,5)P/temsirolimus (a rapamycin analog)-bound open states. These structures, combined with electrophysiology, elucidate the molecular details of ligand binding and provide structural insight into how the TRPML1 channel integrates two distantly bound ligand stimuli and facilitates channel opening.
History
DepositionNov 4, 2021-
Header (metadata) releaseFeb 2, 2022-
Map releaseFeb 2, 2022-
UpdateFeb 23, 2022-
Current statusFeb 23, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7sq6
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_25377.png

Downloads & links

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Map

FileDownload / File: emd_25377.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.025 / Movie #1: 0.025
Minimum - Maximum-0.08014265 - 0.15349865
Average (Standard dev.)0.00031308722 (±0.0062225284)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 239.04 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.830.830.83
M x/y/z288288288
origin x/y/z0.0000.0000.000
length x/y/z239.040239.040239.040
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS288288288
D min/max/mean-0.0800.1530.000

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Supplemental data

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Sample components

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Entire : Mouse Transient receptor potential-mucolipin 1 apo closed state

EntireName: Mouse Transient receptor potential-mucolipin 1 apo closed state
Components
  • Complex: Mouse Transient receptor potential-mucolipin 1 apo closed state
    • Protein or peptide: Mucolipin-1MCOLN1
  • Ligand: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione
  • Ligand: SODIUM IONSodium
  • Ligand: water

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Supramolecule #1: Mouse Transient receptor potential-mucolipin 1 apo closed state

SupramoleculeName: Mouse Transient receptor potential-mucolipin 1 apo closed state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Mucolipin-1

MacromoleculeName: Mucolipin-1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 65.573617 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATPAGRRAS ETERLLTPNP GYGTQVGTSP APTTPTEEED LRRRLKYFFM SPCDKFRAKG RKPCKLMLQV VKILVVTVQL ILFGLSNQL VVTFREENTI AFRHLFLLGY SDGSDDTFAA YTQEQLYQAI FYAVDQYLIL PEISLGRYAY VRGGGGPWAN G SALALCQR ...String:
MATPAGRRAS ETERLLTPNP GYGTQVGTSP APTTPTEEED LRRRLKYFFM SPCDKFRAKG RKPCKLMLQV VKILVVTVQL ILFGLSNQL VVTFREENTI AFRHLFLLGY SDGSDDTFAA YTQEQLYQAI FYAVDQYLIL PEISLGRYAY VRGGGGPWAN G SALALCQR YYHRGHVDPA NDTFDIDPRV VTDCIQVDPP DRPPDIPSED LDFLDGSASY KNLTLKFHKL INVTIHFQLK TI NLQSLIN NEIPDCYTFS ILITFDNKAH SGRIPIRLET KTHIQECKHP SVSRHGDNSF RLLFDVVVIL TCSLSFLLCA RSL LRGFLL QNEFVVFMWR RRGREISLWE RLEFVNGWYI LLVTSDVLTI SGTVMKIGIE AKNLASYDVC SILLGTSTLL VWVG VIRYL TFFHKYNILI ATLRVALPSV MRFCCCVAVI YLGYCFCGWI VLGPYHVKFR SLSMVSECLF SLINGDDMFV TFAAM QAQQ GHSSLVWLFS QLYLYSFISL FIYMVLSLFI ALITGAYDTI KHPGGTGTEK SELQAYIEQC QDSPTSGKFR RGSGSA CSL FCCCGRDSPE DHSLLVN

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Macromolecule #3: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]eth...

MacromoleculeName: 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
Molecular weightTheoretical: 362.422 Da
Chemical component information

ChemComp-AQV:
2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 12 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.9 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: RANDOM ASSIGNMENT
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.32 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 41980

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