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- PDB-9b93: Cryo-EM structure of the human TRPM4 channel in the presence of E... -

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Basic information

Entry
Database: PDB / ID: 9b93
TitleCryo-EM structure of the human TRPM4 channel in the presence of EDTA at 37 degrees Celsius
ComponentsTransient receptor potential cation channel subfamily M member 4
KeywordsTRANSPORT PROTEIN / ion channel / TRP channel
Function / homology
Function and homology information


positive regulation of atrial cardiac muscle cell action potential / positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization / sodium channel complex / regulation of T cell cytokine production / membrane depolarization during AV node cell action potential / metal ion transport / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / negative regulation of bone mineralization / regulation of ventricular cardiac muscle cell action potential ...positive regulation of atrial cardiac muscle cell action potential / positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization / sodium channel complex / regulation of T cell cytokine production / membrane depolarization during AV node cell action potential / metal ion transport / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / negative regulation of bone mineralization / regulation of ventricular cardiac muscle cell action potential / calcium-activated cation channel activity / sodium ion import across plasma membrane / inorganic cation transmembrane transport / dendritic cell chemotaxis / TRP channels / cellular response to ATP / sodium channel activity / monoatomic cation transmembrane transport / regulation of heart rate by cardiac conduction / positive regulation of insulin secretion involved in cellular response to glucose stimulus / protein sumoylation / negative regulation of osteoblast differentiation / positive regulation of fat cell differentiation / positive regulation of heart rate / positive regulation of adipose tissue development / positive regulation of vasoconstriction / calcium-mediated signaling / calcium ion transmembrane transport / calcium channel activity / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of canonical Wnt signaling pathway / positive regulation of cytosolic calcium ion concentration / protein homotetramerization / adaptive immune response / calmodulin binding / neuronal cell body / positive regulation of cell population proliferation / calcium ion binding / endoplasmic reticulum / Golgi apparatus / nucleoplasm / ATP binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
TRPM, SLOG domain / : / SLOG in TRPM / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Transient receptor potential cation channel subfamily M member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsHu, J. / Lu, W. / Du, J.
Funding support United States, 9items
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
McKnight FoundationMcKnight Scholar Award United States
Simons FoundationKlingenstein-Simon Scholar United States
Alfred P. Sloan FoundationSloan Research Fellowship United States
The Pew Charitable TrustsPew Scholar United States
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 2024Provider: repository / Type: Initial release
Revision 1.1May 29, 2024Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 26, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update
Revision 1.3Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily M member 4
B: Transient receptor potential cation channel subfamily M member 4
C: Transient receptor potential cation channel subfamily M member 4
D: Transient receptor potential cation channel subfamily M member 4


Theoretical massNumber of molelcules
Total (without water)537,8264
Polymers537,8264
Non-polymers00
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
Transient receptor potential cation channel subfamily M member 4 / hTRPM4 / Calcium-activated non-selective cation channel 1 / Long transient receptor potential ...hTRPM4 / Calcium-activated non-selective cation channel 1 / Long transient receptor potential channel 4 / LTrpC4 / Melastatin-4


Mass: 134456.484 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPM4, LTRPC4 / Production host: Mammalia (mammals) / References: UniProt: Q8TD43
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: human TRPM4 channel in the presence of EDTA at 37 degrees Celsius
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Mammalia (mammals)
Buffer solutionpH: 8
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1900 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 610000 / Symmetry type: POINT

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