|Entry||Database: PDB / ID: 6pus|
|Title||Human TRPM2 bound to ADPR and calcium|
|Components||Transient receptor potential cation channel subfamily M member 2|
|Keywords||TRANSPORT PROTEIN / TRPM2 channel / ADPR / calcium|
|Function / homology|
Function and homology information
response to purine-containing compound / cellular response to purine-containing compound / mono-ADP-D-ribose binding / manganese ion transmembrane transporter activity / zinc ion transmembrane transport / ligand-gated calcium channel activity / dendritic cell differentiation / cellular response to temperature stimulus / regulation of filopodium assembly / sodium channel activity ...response to purine-containing compound / cellular response to purine-containing compound / mono-ADP-D-ribose binding / manganese ion transmembrane transporter activity / zinc ion transmembrane transport / ligand-gated calcium channel activity / dendritic cell differentiation / cellular response to temperature stimulus / regulation of filopodium assembly / sodium channel activity / calcium ion transmembrane import into cytosol / estrous cycle / TRP channels / regulation of actin cytoskeleton reorganization / response to hydroperoxide / dendritic cell chemotaxis / positive regulation of oxidative stress-induced neuron death / cation transmembrane transport / temperature homeostasis / calcium-release channel activity / calcium ion import across plasma membrane / ficolin-1-rich granule membrane / calcium-mediated signaling using intracellular calcium source / tertiary granule membrane / release of sequestered calcium ion into cytosol / positive regulation of insulin secretion / specific granule membrane / cation channel activity / cellular response to calcium ion / calcium ion transmembrane transport / calcium channel activity / calcium ion transport / cytoplasmic vesicle membrane / cellular response to hydrogen peroxide / perikaryon / response to heat / lysosomal membrane / protein homotetramerization / lysosome / neuron projection / Neutrophil degranulation / calcium ion binding / integral component of plasma membrane / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily M member 2 / SLOG in TRPM / TRPM, SLOG domain / NUDIX hydrolase domain / Nudix hydrolase domain profile. / NUDIX hydrolase-like domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
ADENOSINE-5-DIPHOSPHORIBOSE / Transient receptor potential cation channel subfamily M member 2
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å|
|Authors||Du, J. / Lu, W. / Huang, Y.|
|Funding support|| United States, 1items |
|Citation||Journal: Elife / Year: 2019|
Title: Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel.
Authors: Yihe Huang / Becca Roth / Wei Lü / Juan Du /
Abstract: TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca and ADP ribose (ADPR), an NAD-metabolite ...TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca and ADP ribose (ADPR), an NAD-metabolite produced under oxidative stress and neurodegenerative conditions, suggests a role in neurological disorders. We provide a central concept between triple-site ligand binding and the channel gating of human TRPM2. We show consecutive structural rearrangements and channel activation of TRPM2 induced by binding of ADPR in two indispensable locations, and the binding of Ca in the transmembrane domain. The 8-Br-cADPR-an antagonist of cADPR-binds only to the MHR1/2 domain and inhibits TRPM2 by stabilizing the channel in an apo-like conformation. We conclude that MHR1/2 acts as a orthostatic ligand-binding site for TRPM2. The NUDT9-H domain binds to a second ADPR to assist channel activation in vertebrates, but not necessary in invertebrates. Our work provides insights into the gating mechanism of human TRPM2 and its pharmacology.
|Structure viewer||Molecule: |
Downloads & links
A: Transient receptor potential cation channel subfamily M member 2
C: Transient receptor potential cation channel subfamily M member 2
D: Transient receptor potential cation channel subfamily M member 2
B: Transient receptor potential cation channel subfamily M member 2
Mass: 172280.062 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPM2, EREG1, KNP3, LTRPC2, TRPC7 / Production host: Homo sapiens (human) / References: UniProt: O94759
|Has ligand of interest||N|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: human TRPM2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Homo sapiens (human)|
|Buffer solution||pH: 8|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Details: unspecified|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm|
|Specimen holder||Cryogen: NITROGEN|
|Image recording||Average exposure time: 8 sec. / Electron dose: 6.8 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Image scans||Movie frames/image: 40 / Used frames/image: 1-40|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|3D reconstruction||Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 287184 / Symmetry type: POINT|
|Atomic model building||Protocol: AB INITIO MODEL / Space: REAL|
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