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- PDB-9eky: (+)ML-SI3 bound TRPML2 in a pre-open state -

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Basic information

Entry
Database: PDB / ID: 9eky
Title(+)ML-SI3 bound TRPML2 in a pre-open state
ComponentsMucolipin-2
KeywordsMEMBRANE PROTEIN / TRPML / calcium channel / ion transport / cryo-EM
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
Chem-ZB4 / Mucolipin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.67 Å
AuthorsSchmiege, P. / Li, X.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 18, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 18, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 18, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jun 18, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 2.0Jan 7, 2026Group: Atomic model / Data collection / Database references
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Revision 1.1Jan 7, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mucolipin-2
B: Mucolipin-2
C: Mucolipin-2
D: Mucolipin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)265,7838
Polymers264,0654
Non-polymers1,7184
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-2 / Transient receptor potential channel mucolipin 2 / TRPML2


Mass: 66016.297 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCOLN2 / Production host: Homo sapiens (human) / References: UniProt: Q8IZK6
#2: Chemical
ChemComp-ZB4 / N-{(1S,2S)-2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl}benzenesulfonamide


Mass: 429.576 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H31N3O3S / Feature type: SUBJECT OF INVESTIGATION / Comment: channel blocker, antagonist*YM
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: (+)ML-SI3 bound TRPML2 / 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: 2.67 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 87878 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00515564
ELECTRON MICROSCOPYf_angle_d0.54421028
ELECTRON MICROSCOPYf_dihedral_angle_d13.9335636
ELECTRON MICROSCOPYf_chiral_restr0.0392364
ELECTRON MICROSCOPYf_plane_restr0.0042572

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