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- PDB-9eks: ML2-SA1 bound TRPML1-V432A/A433G in a partially open state -

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Basic information

Entry
Database: PDB / ID: 9eks
TitleML2-SA1 bound TRPML1-V432A/A433G in a partially open state
ComponentsMucolipin-1
KeywordsTRANSPORT PROTEIN / TRPML / calcium channel / ion transport / cryo-EM
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.42 Å
AuthorsSchmiege, P. / Li, X.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 18, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mucolipin-1
B: Mucolipin-1
C: Mucolipin-1
D: Mucolipin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)265,2888
Polymers264,1604
Non-polymers1,1294
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Mucolipin-1 / ML1 / MG-2 / Mucolipidin / Transient receptor potential channel mucolipin 1 / TRPML1


Mass: 66039.883 Da / Num. of mol.: 4 / Mutation: V432A/A433G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCOLN1, ML4, TRPML1, MSTP080 / Production host: Homo sapiens (human) / References: UniProt: Q9GZU1
#2: Chemical
ChemComp-A1BI6 / (3aS,4S,7R,7aS)-3-(2,6-dichlorophenyl)-3a,4,5,6,7,7a-hexahydro-4,7-methano-1,2-benzoxazole


Mass: 282.165 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H13Cl2NO / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: ML2-SA1 bound TRPML1-V432A/A433G / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.42 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 200542 / Symmetry type: POINT

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