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- EMDB-44369: Cryo-EM structure of the human TRPM4 channel in complex with calc... -

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Basic information

Entry
Database: EMDB / ID: EMD-44369
TitleCryo-EM structure of the human TRPM4 channel in complex with calcium, decavanadate and ATP at 37 degrees Celsius
Map data
Sample
  • Complex: Cryo-EM structure of the human TRPM4 channel in complex with calcium, decavanadate and ATP at 37 degrees Celsius
    • Protein or peptide: Transient receptor potential cation channel subfamily M
Keywordsion channel / TRP channel / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsHu J / Lu W / Du J
Funding support United States, 9 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL153219 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS112363 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS111031 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS129804 United States
Other privateMcKnight Scholar Award
Other privateKlingenstein-Simon Scholar
Other privateSloan Research Fellowship
Other privatePew Scholar
American Heart Association24POST1196982 United States
CitationJournal: Nature / Year: 2024
Title: Physiological temperature drives TRPM4 ligand recognition and gating.
Authors: Jinhong Hu / Sung Jin Park / Tyler Walter / Ian J Orozco / Garrett O'Dea / Xinyu Ye / Juan Du / Wei Lü /
Abstract: Temperature profoundly affects macromolecular function, particularly in proteins with temperature sensitivity. However, its impact is often overlooked in biophysical studies that are typically ...Temperature profoundly affects macromolecular function, particularly in proteins with temperature sensitivity. However, its impact is often overlooked in biophysical studies that are typically performed at non-physiological temperatures, potentially leading to inaccurate mechanistic and pharmacological insights. Here we demonstrate temperature-dependent changes in the structure and function of TRPM4, a temperature-sensitive Ca-activated ion channel. By studying TRPM4 prepared at physiological temperature using single-particle cryo-electron microscopy, we identified a 'warm' conformation that is distinct from those observed at lower temperatures. This conformation is driven by a temperature-dependent Ca-binding site in the intracellular domain, and is essential for TRPM4 function in physiological contexts. We demonstrated that ligands, exemplified by decavanadate (a positive modulator) and ATP (an inhibitor), bind to different locations of TRPM4 at physiological temperatures than at lower temperatures, and that these sites have bona fide functional relevance. We elucidated the TRPM4 gating mechanism by capturing structural snapshots of its different functional states at physiological temperatures, revealing the channel opening that is not observed at lower temperatures. Our study provides an example of temperature-dependent ligand recognition and modulation of an ion channel, underscoring the importance of studying macromolecules at physiological temperatures. It also provides a potential molecular framework for deciphering how thermosensitive TRPM channels perceive temperature changes.
History
DepositionApr 1, 2024-
Header (metadata) releaseMay 22, 2024-
Map releaseMay 22, 2024-
UpdateJun 5, 2024-
Current statusJun 5, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44369.png

Downloads & links

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Map

FileDownload / File: emd_44369.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.828 Å
Density
Contour LevelBy AUTHOR: 0.33
Minimum - Maximum-0.23831199 - 0.78044444
Average (Standard dev.)0.0062944186 (±0.052345846)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 317.952 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_44369_additional_1.map
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AxesZYX

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Half map: #1

Fileemd_44369_half_map_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #2

Fileemd_44369_half_map_2.map
Projections & Slices
AxesZYX

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Sample components

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Entire : Cryo-EM structure of the human TRPM4 channel in complex with calc...

EntireName: Cryo-EM structure of the human TRPM4 channel in complex with calcium, decavanadate and ATP at 37 degrees Celsius
Components
  • Complex: Cryo-EM structure of the human TRPM4 channel in complex with calcium, decavanadate and ATP at 37 degrees Celsius
    • Protein or peptide: Transient receptor potential cation channel subfamily M

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Supramolecule #1: Cryo-EM structure of the human TRPM4 channel in complex with calc...

SupramoleculeName: Cryo-EM structure of the human TRPM4 channel in complex with calcium, decavanadate and ATP at 37 degrees Celsius
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transient receptor potential cation channel subfamily M

MacromoleculeName: Transient receptor potential cation channel subfamily M
type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Mammalia (mammals)
SequenceString: MVVPEKEQSW IPKIFKKKTC TTFIVDSTDP GGTLCQCGRP RTAHPAVAME DAFGAAVVTV WDSDAHTTEK PTDAYGELDF TGAGRKHSNF LRLSDRTDPA AVYSLVTRTW GFRAPNLVVS VLGGSGGPVL QTWLQDLLRR GLVRAAQSTG AWIVTGGLHT GIGRHVGVAV ...String:
MVVPEKEQSW IPKIFKKKTC TTFIVDSTDP GGTLCQCGRP RTAHPAVAME DAFGAAVVTV WDSDAHTTEK PTDAYGELDF TGAGRKHSNF LRLSDRTDPA AVYSLVTRTW GFRAPNLVVS VLGGSGGPVL QTWLQDLLRR GLVRAAQSTG AWIVTGGLHT GIGRHVGVAV RDHQMASTGG TKVVAMGVAP WGVVRNRDTL INPKGSFPAR YRWRGDPEDG VQFPLDYNYS AFFLVDDGTH GCLGGENRFR LRLESYISQQ KTGVGGTGID IPVLLLLIDG DEKMLTRIEN ATQAQLPCLL VAGSGGAADC LAETLEDTLA PGSGGARQGE ARDRIRRFFP KGDLEVLQAQ VERIMTRKEL LTVYSSEDGS EEFETIVLKA LVKACGSSEA SAYLDELRLA VAWNRVDIAQ SELFRGDIQW RSFHLEASLM DALLNDRPEF VRLLISHGLS LGHFLTPMRL AQLYSAAPSN SLIRNLLDQA SHSAGTKAPA LKGGAAELRP PDVGHVLRML LGKMCAPRYP SGGAWDPHPG QGFGESMYLL SDKATSPLSL DAGLGQAPWS DLLLWALLLN RAQMAMYFWE MGSNAVSSAL GACLLLRVMA RLEPDAEEAA RRKDLAFKFE GMGVDLFGEC YRSSEVRAAR LLLRRCPLWG DATCLQLAMQ ADARAFFAQD GVQSLLTQKW WGDMASTTPI WALVLAFFCP PLIYTRLITF RKSEEEPTRE ELEFDMDSVI NGEGPVGTAD PAEKTPLGVP RQSGRPGCCG GRCGGRRCLR RWFHFWGAPV TIFMGNVVSY LLFLLLFSRV LLVDFQPAPP GSLELLLYFW AFTLLCEELR QGLSGGGGSL ASGGPGPGHA SLSQRLRLYL ADSWNQCDLV ALTCFLLGVG CRLTPGLYHL GRTVLCIDFM VFTVRLLHIF TVNKQLGPKI VIVSKMMKDV FFFLFFLGVW LVAYGVATEG LLRPRDSDFP SILRRVFYRP YLQIFGQIPQ EDMDVALMEH SNCSSEPGFW AHPPGAQAGT CVSQYANWLV VLLLVIFLLV ANILLVNLLI AMFSYTFGKV QGNSDLYWKA QRYRLIREFH SRPALAPPFI VISHLRLLLR QLCRRPRSPQ PSSPALEHFR VYLSKEAERK LLTWESVHKE NFLLARARDK RESDSERLKR TSQKVDLALK QLGHIREYEQ RLKVLEREVQ QCSRVLGWVA EALSRSALLP PGGPPPPDLP GSKD

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.4000000000000001 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 70000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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