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- EMDB-44259: Cryo-EM structure of the mouse TRPM8 channel in complex with the ... -
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Open data
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Basic information
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Title | Cryo-EM structure of the mouse TRPM8 channel in complex with the antagonist TC-I 2014 and the cooling agonist C3 | |||||||||
![]() | The final full map sharpened with a B factor of -30 | |||||||||
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![]() | TRPM8 / menthol receptor / cold receptor / PI(4 / 5)P2 / cooling agonists / temperature sensing / ion channel / sensory transduction / transient receptor potential ion channel / TRPM8 activation / TRPM8 inhibition / TRPM8 desensitization / TRPM8 antagonists / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() ligand-gated calcium channel activity / TRP channels / thermoception / response to temperature stimulus / response to cold / calcium ion transmembrane transport / calcium channel activity / intracellular calcium ion homeostasis / calcium ion transport / monoatomic ion channel activity ...ligand-gated calcium channel activity / TRP channels / thermoception / response to temperature stimulus / response to cold / calcium ion transmembrane transport / calcium channel activity / intracellular calcium ion homeostasis / calcium ion transport / monoatomic ion channel activity / positive regulation of cold-induced thermogenesis / membrane raft / external side of plasma membrane / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.76 Å | |||||||||
![]() | Yin Y / Park C-G / Zhang F / Fedor J / Feng S / Suo Y / Im W / Lee S-Y | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8. Authors: Ying Yin / Cheon-Gyu Park / Feng Zhang / Justin G Fedor / Shasha Feng / Yang Suo / Wonpil Im / Seok-Yong Lee / ![]() Abstract: Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and ...Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 64.3 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 20.1 KB 20.1 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 11.9 KB | Display | ![]() |
Images | ![]() | 124.5 KB | ||
Filedesc metadata | ![]() | 7.4 KB | ||
Others | ![]() ![]() | 115.9 MB 115.9 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 9b6hMC ![]() 9b6dC ![]() 9b6eC ![]() 9b6fC ![]() 9b6gC ![]() 9b6iC ![]() 9b6jC ![]() 9b6kC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Map
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Annotation | The final full map sharpened with a B factor of -30 | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.08 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Half map A of the final 3D reconstruction
File | emd_44259_half_map_1.map | ||||||||||||
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Annotation | Half map A of the final 3D reconstruction | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map B of the final 3D reconstruction
File | emd_44259_half_map_2.map | ||||||||||||
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Annotation | Half map B of the final 3D reconstruction | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Transient receptor potential cation channel subfamily M member 8
Entire | Name: Transient receptor potential cation channel subfamily M member 8 |
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Components |
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-Supramolecule #1: Transient receptor potential cation channel subfamily M member 8
Supramolecule | Name: Transient receptor potential cation channel subfamily M member 8 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
-Macromolecule #1: Transient receptor potential cation channel subfamily M member 8
Macromolecule | Name: Transient receptor potential cation channel subfamily M member 8 type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 131.548312 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MASFEGARLS MRSRRNGTMG STRTLYSSVS RSTDVSYSDS DLVNFIQANF KKRECVFFTR DSKAMENICK CGYAQSQHIE GTQINQNEK WNYKKHTKEF PTDAFGDIQF ETLGKKGKYL RLSCDTDSET LYELLTQHWH LKTPNLVISV TGGAKNFALK P RMRKIFSR ...String: MASFEGARLS MRSRRNGTMG STRTLYSSVS RSTDVSYSDS DLVNFIQANF KKRECVFFTR DSKAMENICK CGYAQSQHIE GTQINQNEK WNYKKHTKEF PTDAFGDIQF ETLGKKGKYL RLSCDTDSET LYELLTQHWH LKTPNLVISV TGGAKNFALK P RMRKIFSR LIYIAQSKGA WILTGGTHYG LMKYIGEVVR DNTISRNSEE NIVAIGIAAW GMVSNRDTLI RSCDDEGHFS AQ YIMDDFT RDPLYILDNN HTHLLLVDNG CHGHPTVEAK LRNQLEKYIS ERTSQDSNYG GKIPIVCFAQ GGGRETLKAI NTS VKSKIP CVVVEGSGQI ADVIASLVEV EDVLTSSMVK EKLVRFLPRT VSRLPEEEIE SWIKWLKEIL ESSHLLTVIK MEEA GDEIV SNAISYALYK AFSTNEQDKD NWNGQLKLLL EWNQLDLASD EIFTNDRRWE SADLQEVMFT ALIKDRPKFV RLFLE NGLN LQKFLTNEVL TELFSTHFST LVYRNLQIAK NSYNDALLTF VWKLVANFRR SFWKEDRSSR EDLDVELHDA SLTTRH PLQ ALFIWAILQN KKELSKVIWE QTKGCTLAAL GASKLLKTLA KVKNDINAAG ESEELANEYE TRAVELFTEC YSNDEDL AE QLLVYSCEAW GGSNCLELAV EATDQHFIAQ PGVQNFLSKQ WYGEISRDTK NWKIILCLFI IPLVGCGLVS FRKKPIDK H KKLLWYYVAF FTSPFVVFSW NVVFYIAFLL LFAYVLLMDF HSVPHTPELI LYALVFVLFC DEVRQWYMNG VNYFTDLWN VMDTLGLFYF IAGIVFRLHS SNKSSLYSGR VIFCLDYIIF TLRLIHIFTV SRNLGPKIIM LQRMLIDVFF FLFLFAVWMV AFGVARQGI LRQNEQRWRW IFRSVIYEPY LAMFGQVPSD VDSTTYDFSH CTFSGNESKP LCVELDEHNL PRFPEWITIP L VCIYMLST NILLVNLLVA MFGYTVGIVQ ENNDQVWKFQ RYFLVQEYCN RLNIPFPFVV FAYFYMVVKK CFKCCCKEKN ME SNACCFR NEDNETLAWE GVMKENYLVK INTKANDNSE EMRHRFRQLD SKLNDLKSLL KEIANNIKSN SLEVLFQGPD YKD DDDKAH HHHHHHHHH UniProtKB: Transient receptor potential cation channel subfamily M member 8 |
-Macromolecule #2: 3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimida...
Macromolecule | Name: 3-{7-(trifluoromethyl)-5-[2-(trifluoromethyl)phenyl]-1H-benzimidazol-2-yl}-1-oxa-2-azaspiro[4.5]dec-2-ene type: ligand / ID: 2 / Number of copies: 4 / Formula: T14 |
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Molecular weight | Theoretical: 467.407 Da |
Chemical component information | ![]() ChemComp-T14: |
-Macromolecule #3: CHOLESTEROL HEMISUCCINATE
Macromolecule | Name: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 12 / Formula: Y01 |
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Molecular weight | Theoretical: 486.726 Da |
Chemical component information | ![]() ChemComp-Y01: |
-Macromolecule #4: nonyl(oxo)di(propan-2-yl)-lambda~5~-phosphane
Macromolecule | Name: nonyl(oxo)di(propan-2-yl)-lambda~5~-phosphane / type: ligand / ID: 4 / Number of copies: 4 / Formula: ULO |
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Molecular weight | Theoretical: 260.396 Da |
Chemical component information | ![]() ChemComp-ULO: |
-Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 4 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2 / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293.15 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 14226 / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 81000 |
Sample stage | Specimen 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
-Atomic model buiding 1
Initial model | Chain - Source name: Other / Chain - Initial model type: experimental model Details: Another structural model from this study was used as the initial model for model building. |
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Refinement | Space: REAL / Protocol: RIGID BODY FIT |
Output model | ![]() PDB-9b6h: |