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- EMDB-48143: ML2-SA1 bound TRPML2 in a pre-open state -

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Basic information

Entry
Database: EMDB / ID: EMD-48143
TitleML2-SA1 bound TRPML2 in a pre-open state
Map dataML2-SA1 bound TRPML2 in a pre-open state
Sample
  • Complex: ML2-SA1 bound TRPML2
    • Protein or peptide: Mucolipin-2
  • Ligand: (3aS,4S,7R,7aS)-3-(2,6-dichlorophenyl)-3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzoxazole
KeywordsTRPML / calcium channel / ion transport / membrane protein
Function / homology
Function and homology information


positive regulation of macrophage inflammatory protein 1 alpha production / macrophage migration / NAADP-sensitive calcium-release channel activity / positive regulation of chemokine (C-C motif) ligand 5 production / iron ion transmembrane transporter activity / neutrophil migration / positive regulation of monocyte chemotactic protein-1 production / positive regulation of chemokine (C-X-C motif) ligand 2 production / TRP channels / calcium ion transmembrane transport ...positive regulation of macrophage inflammatory protein 1 alpha production / macrophage migration / NAADP-sensitive calcium-release channel activity / positive regulation of chemokine (C-C motif) ligand 5 production / iron ion transmembrane transporter activity / neutrophil migration / positive regulation of monocyte chemotactic protein-1 production / positive regulation of chemokine (C-X-C motif) ligand 2 production / TRP channels / calcium ion transmembrane transport / calcium channel activity / recycling endosome membrane / late endosome membrane / protein transport / adaptive immune response / lysosome / innate immune response / 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: 2.45 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)R35GM149533 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_48143.png

Downloads & links

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Map

FileDownload / File: emd_48143.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationML2-SA1 bound TRPML2 in a pre-open state
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 320 pix.
= 236.16 Å		0.74 Å/pix.
x 320 pix.
= 236.16 Å		0.74 Å/pix.
x 320 pix.
= 236.16 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: 0.065
Minimum - Maximum-0.30129376 - 0.5544928
Average (Standard dev.)0.0008857978 (±0.019199766)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 236.15999 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_48143_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_48143_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : ML2-SA1 bound TRPML2

EntireName: ML2-SA1 bound TRPML2
Components
  • Complex: ML2-SA1 bound TRPML2
    • Protein or peptide: Mucolipin-2
  • Ligand: (3aS,4S,7R,7aS)-3-(2,6-dichlorophenyl)-3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzoxazole

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Supramolecule #1: ML2-SA1 bound TRPML2

SupramoleculeName: ML2-SA1 bound TRPML2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Mucolipin-2

MacromoleculeName: Mucolipin-2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.016297 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MARQPYRFPQ ARIPERGSGV FRLTVRNAMA HRDSEMKEEC LREDLKFYFM SPCEKYRARR QIPWKLGLQI LKIVMVTTQL VRFGLSNQL VVAFKEDNTV AFKHLFLKGY SGTDEDDYSC SVYTQEDAYE SIFFAINQYH QLKDITLGTL GYGENEDNRI G LKVCKQHY ...String:
MARQPYRFPQ ARIPERGSGV FRLTVRNAMA HRDSEMKEEC LREDLKFYFM SPCEKYRARR QIPWKLGLQI LKIVMVTTQL VRFGLSNQL VVAFKEDNTV AFKHLFLKGY SGTDEDDYSC SVYTQEDAYE SIFFAINQYH QLKDITLGTL GYGENEDNRI G LKVCKQHY KKGTMFPSNE TLNIDNDVEL DCVQLDLQDL SKKPPDWKNS SFFRLEFYRL LQVEISFHLK GIDLQTIHSR EL PDCYVFQ NTIIFDNKAH SGKIKIYFDS DAKIEECKDL NIFGSTQKNA QYVLVFDAFV IVICLASLIL CTRSIVLALR LRK RFLNFF LEKYKRPVCD TDQWEFINGW YVLVIISDLM TIIGSILKME IKAKNLTNYD LCSIFLGTST LLVWVGVIRY LGYF QAYNV LILTMQASLP KVLRFCACAG MIYLGYTFCG WIVLGPYHDK FENLNTVAEC LFSLVNGDDM FATFAQIQQK SILVW LFSR LYLYSFISLF IYMILSLFIA LITDSYDTIK KFQQNGFPET DLQEFLKECS SKEEYQKESS AFLSCICCRR RKRSDD HLI PIS

UniProtKB: Mucolipin-2

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Macromolecule #2: (3aS,4S,7R,7aS)-3-(2,6-dichlorophenyl)-3a,4,5,6,7,7a-hexahydro-4,...

MacromoleculeName: (3aS,4S,7R,7aS)-3-(2,6-dichlorophenyl)-3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzoxazole
type: ligand / ID: 2 / Number of copies: 4 / Formula: A1BI6
Molecular weightTheoretical: 282.165 Da

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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: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 273537
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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