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- EMDB-52249: TRPML1 in complex with compound 10 -

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Basic information

Entry
Database: EMDB / ID: EMD-52249
TitleTRPML1 in complex with compound 10
Map dataCryoSPARC sharpened masked filtered map
Sample
  • Complex: Mucolipin-1
    • Protein or peptide: Mucolipin-1
  • Ligand: HEXANE
  • Ligand: DODECANE
  • Ligand: N-OCTANE
  • Ligand: (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate
  • Ligand: HEXADECANE
  • Ligand: DECANE
  • Ligand: N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]phenyl]benzenesulfonamide
  • Ligand: water
KeywordsIon channel / MEMBRANE 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 / phagosome maturation / NAADP-sensitive calcium-release channel activity / iron ion transmembrane transporter activity / ligand-gated calcium channel activity / cellular response to pH / Transferrin endocytosis and recycling / iron ion transmembrane transport ...positive regulation of lysosome organization / calcium ion export / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / phagosome maturation / NAADP-sensitive calcium-release channel activity / iron ion transmembrane transporter activity / ligand-gated calcium channel activity / cellular response to pH / Transferrin endocytosis and recycling / iron ion transmembrane transport / monoatomic anion channel activity / TRP channels / sodium channel activity / autophagosome maturation / monoatomic cation transport / potassium channel activity / phagocytic cup / monoatomic cation channel activity / 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: 2.1 Å
AuthorsReeks J / Mahajan P / Clark M / Cowan SR / Di Daniel E / Earl CP / Fisher S / Holvey RS / Jackson SM / Lloyd-Evans E ...Reeks J / Mahajan P / Clark M / Cowan SR / Di Daniel E / Earl CP / Fisher S / Holvey RS / Jackson SM / Lloyd-Evans E / Morgillo CM / Mortenson PN / O'Reilly M / Richardson CJ / Schopf P / Tams DM / Waller-Evans H / Ward SE / Whibley S / Williams PA / Johnson CN
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Structure / Year: 2025
Title: High throughput cryo-EM provides structural understanding for modulators of the lysosomal ion channel TRPML1.
Authors: Judith Reeks / Pravin Mahajan / Mellissa Clark / Suzanna R Cowan / Elena Di Daniel / Christopher P Earl / Samantha Fisher / Rhian S Holvey / Scott M Jackson / Emyr Lloyd-Evans / Carmine M ...Authors: Judith Reeks / Pravin Mahajan / Mellissa Clark / Suzanna R Cowan / Elena Di Daniel / Christopher P Earl / Samantha Fisher / Rhian S Holvey / Scott M Jackson / Emyr Lloyd-Evans / Carmine M Morgillo / Paul N Mortenson / Marc O'Reilly / Caroline J Richardson / Patrick Schöpf / Daniel M Tams / Helen Waller-Evans / Simon E Ward / Stuart Whibley / Pamela A Williams / Christopher N Johnson /
Abstract: Access to high-resolution structural data for protein-ligand complexes is a prerequisite for structure-based medicinal chemistry, where the ability to iterate cycles of design-structure-redesign is ...Access to high-resolution structural data for protein-ligand complexes is a prerequisite for structure-based medicinal chemistry, where the ability to iterate cycles of design-structure-redesign is highly desirable. For proteins refractory to X-ray crystallography, such as integral membrane proteins, enablement of high throughput structure determination by cryoelectron microscopy (cryo-EM) has the potential to be transformational for structure-based design. We have applied such an approach to the lysosomal ion channel transient receptor potential mucolipin 1 (TRPML1) in complex with ten chemically diverse modulators, both agonists and antagonists. The resulting depth of high-resolution structural data generated provides important insights into protein-ligand structure-function relationships, including mechanistic understanding of ligand-induced channel pore opening and closing. Moreover, the knowledge gained has the potential to support iterative design cycles toward improved modulators of this important biological target.
History
DepositionDec 4, 2024-
Header (metadata) releaseJun 4, 2025-
Map releaseJun 4, 2025-
UpdateDec 17, 2025-
Current statusDec 17, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52249.png

Downloads & links

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Map

FileDownload / File: emd_52249.map.gz / Format: CCP4 / Size: 783.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoSPARC sharpened masked filtered map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.64 Å/pix.
x 590 pix.
= 379.429 Å		0.64 Å/pix.
x 590 pix.
= 379.429 Å		0.64 Å/pix.
x 590 pix.
= 379.429 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6431 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.471
Minimum - Maximum-1.6300455 - 3.1949878
Average (Standard dev.)0.0020435404 (±0.041963156)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions590590590
Spacing590590590
CellA=B=C: 379.42902 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_52249_msk_1.map
Projections & Slices
AxesZYX

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Additional map: CryoSPARC sharpened unmasked unfiltered map

Fileemd_52249_additional_1.map
AnnotationCryoSPARC sharpened unmasked unfiltered map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Additional map: CryoSPARC sharpened masked filtered map rescaled to 0.5 A/pix

Fileemd_52249_additional_2.map
AnnotationCryoSPARC sharpened masked filtered map rescaled to 0.5 A/pix
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: CryoSPARC non-uniform refinement half map 1

Fileemd_52249_half_map_1.map
AnnotationCryoSPARC non-uniform refinement half map 1
Projections & Slices
AxesZYX

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Half map: CryoSPARC non-uniform refinement half map 2

Fileemd_52249_half_map_2.map
AnnotationCryoSPARC non-uniform refinement half map 2
Projections & Slices
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Sample components

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Entire : Mucolipin-1

EntireName: Mucolipin-1
Components
  • Complex: Mucolipin-1
    • Protein or peptide: Mucolipin-1
  • Ligand: HEXANE
  • Ligand: DODECANE
  • Ligand: N-OCTANE
  • Ligand: (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate
  • Ligand: HEXADECANE
  • Ligand: DECANE
  • Ligand: N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]phenyl]benzenesulfonamide
  • Ligand: water

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Supramolecule #1: Mucolipin-1

SupramoleculeName: Mucolipin-1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 281 KDa

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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: 70.518469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MHHHHHHHHG GSDYKDHDGD YKDHDIDYKD DDDKGGSGGS ENLYFQGPGT APAGPRGSET ERLLTPNPGY GTQAGPSPAP PTPPEEEDL RRRLKYFFMS PCDKFRAKGR KPCKLMLQVV KILVVTVQLI LFGLSNQLAV TFREENTIAF RHLFLLGYSD G ADDTFAAY ...String:
MHHHHHHHHG GSDYKDHDGD YKDHDIDYKD DDDKGGSGGS ENLYFQGPGT APAGPRGSET ERLLTPNPGY GTQAGPSPAP PTPPEEEDL RRRLKYFFMS PCDKFRAKGR KPCKLMLQVV KILVVTVQLI LFGLSNQLAV TFREENTIAF RHLFLLGYSD G ADDTFAAY TREQLYQAIF HAVDQYLALP DVSLGRYAYV RGGGDPWTNG SGLALCQRYY HRGHVDPAND TFDIDPMVVT DC IQVDPPE RPPPPPSDDL TLLESSSSYK NLTLKFHKLV NVTIHFRLKT INLQSLINNE IPDCYTFSVL ITFDNKAHSG RIP ISLETQ AHIQECKHPS VFQHGDNSFR LLFDVVVILT CSLSFLLCAR SLLRGFLLQN EFVGFMWRQR GRVISLWERL EFVN GWYIL LVTSDVLTIS GTIMKIGIEA KNLASYDVCS ILLGTSTLLV WVGVIRYLTF FHNYNILIAT LRVALPSVMR FCCCV AVIY LGYCFCGWIV LGPYHVKFRS LSMVSECLFS LINGDDMFVT FAAMQAQQGR SSLVWLFSQL YLYSFISLFI YMVLSL FIA LITGAYDTIK HPGGAGAEES ELQAYIAQCQ DSPTSGKFRR GSGSACSLLC CCGRDPSEEH SLLVN

UniProtKB: Mucolipin-1

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Macromolecule #3: HEXANE

MacromoleculeName: HEXANE / type: ligand / ID: 3 / Number of copies: 8 / Formula: HEX
Molecular weightTheoretical: 86.175 Da
Chemical component information

ChemComp-HEX:
HEXANE

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Macromolecule #4: DODECANE

MacromoleculeName: DODECANE / type: ligand / ID: 4 / Number of copies: 12 / Formula: D12
Molecular weightTheoretical: 170.335 Da
Chemical component information

ChemComp-D12:
DODECANE

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Macromolecule #5: N-OCTANE

MacromoleculeName: N-OCTANE / type: ligand / ID: 5 / Number of copies: 8 / Formula: OCT
Molecular weightTheoretical: 114.229 Da
Chemical component information

ChemComp-OCT:
N-OCTANE

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Macromolecule #6: (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bi...

MacromoleculeName: (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate
type: ligand / ID: 6 / Number of copies: 4 / Formula: EUJ
Molecular weightTheoretical: 746.566 Da
Chemical component information

ChemComp-EUJ:
(2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate

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Macromolecule #7: HEXADECANE

MacromoleculeName: HEXADECANE / type: ligand / ID: 7 / Number of copies: 4 / Formula: R16
Molecular weightTheoretical: 226.441 Da
Chemical component information

ChemComp-R16:
HEXADECANE

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Macromolecule #8: DECANE

MacromoleculeName: DECANE / type: ligand / ID: 8 / Number of copies: 4 / Formula: D10
Molecular weightTheoretical: 142.282 Da
Chemical component information

ChemComp-D10:
DECANE

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Macromolecule #9: N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]phenyl]benzenesulfonamide

MacromoleculeName: N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]phenyl]benzenesulfonamide
type: ligand / ID: 9 / Number of copies: 4 / Formula: A1IV4
Molecular weightTheoretical: 423.528 Da

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Macromolecule #10: water

MacromoleculeName: water / type: ligand / ID: 10 / Number of copies: 296 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration5 mg/mL
BufferpH: 7
Component:
ConcentrationName
20.0 mMHEPES
150.0 mMSodium chloride
0.0052 %GDN
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Average electron dose: 39.08 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 120000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware:
Namedetails
CTFFIND (ver. 4)For initial estimation
cryoSPARC (ver. 4)For CTF refinement

Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4) / Number images used: 398353
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4)

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Atomic model buiding 1

Initial modelChain - Source name: Other / Chain - Initial model type: experimental model / Details: In house structure
RefinementSpace: REAL / Overall B value: 62
Output model

PDB-9hlb:
TRPML1 in complex with compound 10

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