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- EMDB-23828: Structure of human TRPML1 with ML-SI3 -

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Basic information

Entry
Database: EMDB / ID: EMD-23828
TitleStructure of human TRPML1 with ML-SI3
Map dataStructure of human TRPML1 with ML-SI3
Sample
  • Complex: TRPML1 complex with ML-SI3
    • Protein or peptide: Mucolipin-1MCOLN1
  • Ligand: N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide
  • Ligand: 1,2-Distearoyl-sn-glycerophosphoethanolamine
Function / homology
Function and homology information


calcium ion export / positive regulation of lysosome organization / iron ion transmembrane transporter activity / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / NAADP-sensitive calcium-release channel activity / phagosome maturation / transferrin transport / Transferrin endocytosis and recycling / cellular response to pH / ligand-gated calcium channel activity ...calcium ion export / positive regulation of lysosome organization / iron ion transmembrane transporter activity / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / NAADP-sensitive calcium-release channel activity / phagosome maturation / transferrin transport / Transferrin endocytosis and recycling / cellular response to pH / ligand-gated calcium channel activity / TRP channels / phagocytic cup / autophagosome maturation / monoatomic cation transport / localization / 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 / lysosome / receptor complex / endosome membrane / 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 speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsSchmiege P / Li X
CitationJournal: 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
DepositionApr 12, 2021-
Header (metadata) releaseJun 16, 2021-
Map releaseJun 16, 2021-
UpdateNov 17, 2021-
Current statusNov 17, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.014
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.014
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7mgl
  • Surface level: 0.014
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23828.png

Downloads & links

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Map

FileDownload / File: emd_23828.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of human TRPML1 with ML-SI3
Voxel sizeX=Y=Z: 0.66 Å
Density
Contour LevelBy AUTHOR: 0.011 / Movie #1: 0.014
Minimum - Maximum-0.06465807 - 0.113241866
Average (Standard dev.)3.551257e-05 (±0.0037019697)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions350350350
Spacing350350350
CellA=B=C: 231.00002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.660.660.66
M x/y/z350350350
origin x/y/z0.0000.0000.000
length x/y/z231.000231.000231.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ380380380
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS350350350
D min/max/mean-0.0650.1130.000

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Supplemental data

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Sample components

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Entire : TRPML1 complex with ML-SI3

EntireName: TRPML1 complex with ML-SI3
Components
  • Complex: TRPML1 complex with ML-SI3
    • Protein or peptide: Mucolipin-1MCOLN1
  • Ligand: N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide
  • Ligand: 1,2-Distearoyl-sn-glycerophosphoethanolamine

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Supramolecule #1: TRPML1 complex with ML-SI3

SupramoleculeName: TRPML1 complex with ML-SI3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
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: Homo sapiens (human)
Molecular weightTheoretical: 65.084996 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #2: N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzen...

MacromoleculeName: N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: ZB4
Molecular weightTheoretical: 429.576 Da
Chemical component information

ChemComp-ZB4:
N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide / channel blocker, antagonist*YM / ML-SI3

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Macromolecule #3: 1,2-Distearoyl-sn-glycerophosphoethanolamine

MacromoleculeName: 1,2-Distearoyl-sn-glycerophosphoethanolamine / type: ligand / ID: 3 / Number of copies: 4 / Formula: 3PE
Molecular weightTheoretical: 748.065 Da
Chemical component information

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM / Phosphatidylethanolamine

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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: 4.5
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: DARK FIELD
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: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 508465

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