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- EMDB-48136: (+)ML-SI3 bound TRPML1-V432A/A433G in a partially open state -

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Basic information

Entry
Database: EMDB / ID: EMD-48136
Title(+)ML-SI3 bound TRPML1-V432A/A433G in a partially open state
Map data
Sample
  • Complex: (+)ML-SI3 bound TRPML1-V432A/A433G
    • Protein or peptide: Mucolipin-1
KeywordsTRPML / calcium channel / ion transport / cryo-EM / TRANSPORT PROTEIN
Function / homology
Function and homology information


positive regulation of lysosome organization / calcium ion export / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / NAADP-sensitive calcium-release channel activity / phagosome maturation / iron ion transmembrane transporter activity / ligand-gated calcium channel activity / Transferrin endocytosis and recycling / iron ion transmembrane transport / cellular response to pH ...positive regulation of lysosome organization / calcium ion export / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / NAADP-sensitive calcium-release channel activity / phagosome maturation / iron ion transmembrane transporter activity / ligand-gated calcium channel activity / Transferrin endocytosis and recycling / iron ion transmembrane transport / cellular response to pH / monoatomic anion channel activity / TRP channels / sodium channel activity / autophagosome maturation / monoatomic cation transport / potassium channel activity / monoatomic cation channel activity / phagocytic cup / release of sequestered calcium ion into cytosol / cellular response to calcium ion / transferrin transport / cell projection / calcium ion transmembrane transport / calcium channel activity / phagocytic vesicle membrane / late endosome membrane / late endosome / protein homotetramerization / adaptive immune response / lysosome / receptor complex / endosome membrane / lysosomal membrane / intracellular membrane-bounded organelle / lipid binding / Golgi apparatus / nucleoplasm / identical protein binding / membrane / plasma membrane
Similarity search - Function
: / Mucolipin / : / Mucolipin, extracytosolic domain / Polycystin cation channel, PKD1/PKD2 / Polycystin cation channel
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.35 Å
AuthorsSchmiege P / Li X
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM149533 United States
CitationJournal: Nat Commun / Year: 2025
Title: TRPML2 in distinct states reveals the activation and modulation principles of the TRPML family.
Authors: Philip Schmiege / Dawid Jaślan / Michael Fine / Nidish Ponath Sadanandan / Alexandra Hatton / Nadia Elghobashi-Meinhardt / Christian Grimm / Xiaochun Li /
Abstract: TRPML2 activity is critical for endolysosomal integrity and chemokine secretion, and can be modulated by various ligands. Interestingly, two ML-SI3 isomers regulate TRPML2 oppositely. The molecular ...TRPML2 activity is critical for endolysosomal integrity and chemokine secretion, and can be modulated by various ligands. Interestingly, two ML-SI3 isomers regulate TRPML2 oppositely. The molecular mechanism underlying this unique isomeric preference as well as the TRPML2 agonistic mechanism remains unknown. Here, we present six cryo-EM structures of human TRPML2 in distinct states revealing that the π-bulge of the S6 undergoes a π-α transition upon agonist binding, highlighting the remarkable role of the π-bulge in ion channel regulation. Moreover, we identify that PI(3,5)P allosterically affects the pose of ML2-SA1, a TRPML2 specific activator, resulting in an open channel without the π-α transition. Functional and structural studies show that mutating the S5 of TRPML1 to that of TRPML2 enables the mutated TRPML1 to be activated by (+)ML-SI3 and ML2-SA1. Thus, our work elucidates the activation mechanism of TRPML channels and paves the way for the development of selective TRPML modulators.
History
DepositionDec 3, 2024-
Header (metadata) releaseJun 18, 2025-
Map releaseJun 18, 2025-
UpdateJan 7, 2026-
Current statusJan 7, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48136.png

Downloads & links

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Map

FileDownload / File: emd_48136.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 360 pix.
= 265.68 Å		0.74 Å/pix.
x 360 pix.
= 265.68 Å		0.74 Å/pix.
x 360 pix.
= 265.68 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.738 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.096
Minimum - Maximum-0.4078802 - 0.7144991
Average (Standard dev.)0.00057907595 (±0.022659002)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 265.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_48136_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_48136_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : (+)ML-SI3 bound TRPML1-V432A/A433G

EntireName: (+)ML-SI3 bound TRPML1-V432A/A433G
Components
  • Complex: (+)ML-SI3 bound TRPML1-V432A/A433G
    • Protein or peptide: Mucolipin-1

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Supramolecule #1: (+)ML-SI3 bound TRPML1-V432A/A433G

SupramoleculeName: (+)ML-SI3 bound TRPML1-V432A/A433G / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: 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: 66.039883 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKT APAGPRGSET ERLLTPNPGY GTQAGPSPAP PTPPEEEDLR RRLKYFFMSP CDKFRAKGRK PCKLMLQVVK ILVVTVQLI LFGLSNQLAV TFREENTIAF RHLFLLGYSD GADDTFAAYT REQLYQAIFH AVDQYLALPD VSLGRYAYVR G GGDPWTNG ...String:
MDYKDDDDKT APAGPRGSET ERLLTPNPGY GTQAGPSPAP PTPPEEEDLR RRLKYFFMSP CDKFRAKGRK PCKLMLQVVK ILVVTVQLI LFGLSNQLAV TFREENTIAF RHLFLLGYSD GADDTFAAYT REQLYQAIFH AVDQYLALPD VSLGRYAYVR G GGDPWTNG SGLALCQRYY HRGHVDPAND TFDIDPMVVT DCIQVDPPER PPPPPSDDLT LLESSSSYKN LTLKFHKLVN VT IHFRLKT INLQSLINNE IPDCYTFSVL ITFDNKAHSG RIPISLETQA HIQECKHPSV FQHGDNSFRL LFDVVVILTC SLS FLLCAR SLLRGFLLQN EFVGFMWRQR GRVISLWERL EFVNGWYILL VTSDVLTISG TIMKIGIEAK NLASYDVCSI LLGT STLLV WVGVIRYLTF FHNYNILIAT LRVALPSVMR FCCCAGVIYL GYCFCGWIVL GPYHVKFRSL SMVSECLFSL INGDD MFVT FAAMQAQQGR SSLVWLFSQL YLYSFISLFI YMVLSLFIAL ITGAYDTIKH PGGAGAEESE LQAYIAQCQD SPTSGK FRR GSGSACSLLC CCGRDPSEEH SLLVN

UniProtKB: Mucolipin-1

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.35 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 94982
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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