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- PDB-9z26: Cryo-EM structure of human TRPM4 channel in complex with calcium ... -

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Basic information

Entry
Database: PDB / ID: 9z26
TitleCryo-EM structure of human TRPM4 channel in complex with calcium and NBA at 37 degrees Celsius (monomeric TMD-focused map with best-resolved NBA density)
ComponentsTransient receptor potential cation channel subfamily M member 4
KeywordsMEMBRANE 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 / negative regulation of bone mineralization / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / metal ion transport / 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 / negative regulation of bone mineralization / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / membrane depolarization during Purkinje myocyte cell action potential / metal ion transport / regulation of ventricular cardiac muscle cell action potential / calcium-activated cation channel activity / sodium ion import across plasma membrane / dendritic cell chemotaxis / TRP channels / sodium channel activity / cellular response to ATP / regulation of heart rate by cardiac conduction / monoatomic cation transmembrane transport / positive regulation of fat cell differentiation / protein sumoylation / positive regulation of vasoconstriction / negative regulation of osteoblast differentiation / positive regulation of heart rate / positive regulation of adipose tissue development / positive regulation of insulin secretion involved in cellular response to glucose stimulus / calcium-mediated signaling / calcium ion transmembrane transport / calcium channel activity / transmembrane transport / positive regulation of canonical Wnt signaling pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / Golgi apparatus / endoplasmic reticulum / ATP binding / membrane / identical protein binding / plasma membrane
Similarity search - Function
TRPM, SLOG domain / : / : / SLOG in TRPM / TRPM2-like domain / 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: 2.9 Å
AuthorsJinhong, H. / Wei, L. / Juan, D.
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)R01NS129804 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)R01NS112363 United States
Other privateMcKnight Scholar Award United States
Other privateKlingenstein-Simon Scholar Award United States
Other privateSloan Research Fellowship United States
Other privatePew Scholar in the Biomedical Sciences United States
American Heart Association24POST1196982 United States
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Temperature and intrinsic Ca reshape TRPM4 pharmacology.
Authors: Jinhong Hu / Sofia Ievleva / Sung Jin Park / Junuk Lee / Jie Cheng / Garrett O'Dea / Jiangnan Sheng / Juan Du / Wei Lü /
Abstract: Proteins operate in dynamic environments where ions, lipids and temperature collectively define their properties, yet most studies rely on simplified conditions that overlook these intrinsic ...Proteins operate in dynamic environments where ions, lipids and temperature collectively define their properties, yet most studies rely on simplified conditions that overlook these intrinsic variables. Here we show two such factors-temperature and Ca-remodel the function and pharmacology of TRPM4, an ion channel implicated in cardiac conduction, immune regulation, cancer and intestinal-fluid homeostasis. At physiological temperature and Ca, TPPO-previously considered a selective TRPM5 inhibitor inactive toward TRPM4-potently activates TRPM4, revealing strong synergy among temperature, Ca and ligand binding. By contrast, Necrocide-1, a necroptotic activator targeting the same binding pocket, defies this logic: it opens TRPM4 without Ca but is antagonized by Ca. Meanwhile, the inhibitors NBA and CBA engage a nearby pocket, locking the channel in a non-conductive pre-open state. Our findings highlight that even rigid binding pockets can exhibit temperature-dependent ligand recognition, revealing hidden pharmacology and informing selective, environment-aware therapeutic strategies.
History
DepositionNov 4, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2026Group: Data collection / Database references / Category: citation / em_admin
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Revision 1.1Jun 17, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
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Revision 1.2Jun 24, 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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Revision 1.3Jul 1, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,8523
Polymers134,4561
Non-polymers3962
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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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.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPM4, LTRPC4 / Production host: Homo sapiens (human) / References: UniProt: Q8TD43
#2: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-A1H0C / 4-chloranyl-2-(2-naphthalen-1-yloxyethanoylamino)benzoic acid


Mass: 355.772 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H14ClNO4 / Feature type: SUBJECT OF INVESTIGATION
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: human TRPM4 channel in complex with calcium and NBA at 37 degrees Celsius
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
13RELION53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 239108 / Symmetry type: POINT
RefinementHighest resolution: 2.9 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033035
ELECTRON MICROSCOPYf_angle_d0.4114137
ELECTRON MICROSCOPYf_dihedral_angle_d10.3021068
ELECTRON MICROSCOPYf_chiral_restr0.032465
ELECTRON MICROSCOPYf_plane_restr0.006518

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