|Entry||Database: PDB / ID: 6mj2|
|Title||Human TRPM2 ion channel in a calcium- and ADPR-bound state|
|Components||Transient receptor potential cation channel subfamily M member 2|
|Keywords||MEMBRANE PROTEIN / Channel / TRPM2 / TRP / ADPR / ADP-ribose / NUDT9H / NUDT9 / calcium / ion channel|
|Function / homology|
Function and homology information
cellular response to purine-containing compound / response to purine-containing compound / mono-ADP-D-ribose binding / zinc ion transmembrane transport / ligand-gated calcium channel activity / dendritic cell differentiation / cellular response to temperature stimulus / cation transmembrane transport / regulation of filopodium assembly / sodium channel activity ...cellular response to purine-containing compound / response to purine-containing compound / mono-ADP-D-ribose binding / zinc ion transmembrane transport / ligand-gated calcium channel activity / dendritic cell differentiation / cellular response to temperature stimulus / cation transmembrane transport / regulation of filopodium assembly / sodium channel activity / calcium ion transmembrane import into cytosol / TRP channels / regulation of actin cytoskeleton reorganization / dendritic cell chemotaxis / temperature homeostasis / calcium-release channel activity / calcium ion import across plasma membrane / ficolin-1-rich granule membrane / tertiary granule membrane / release of sequestered calcium ion into cytosol / calcium-mediated signaling using intracellular calcium source / specific granule membrane / cation channel activity / cellular response to calcium ion / calcium ion transmembrane transport / calcium channel activity / cell projection / calcium ion transport / cytoplasmic vesicle membrane / cellular response to hydrogen peroxide / lysosomal membrane / perikaryon / protein homotetramerization / neutrophil degranulation / lysosome / Neutrophil degranulation / calcium ion binding / integral component of plasma membrane / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily M member 2 / TRPM, SLOG domain / SLOG in TRPM / NUDIX hydrolase domain / Nudix hydrolase domain profile. / NUDIX hydrolase-like domain superfamily / Ion transport protein / Ion transport domain
Similarity search - Domain/homology
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: 6.36 Å|
|Authors||Wang, L. / Fu, T.M. / Xia, S. / Wu, H.|
|Citation||Journal: Science / Year: 2018|
Title: Structures and gating mechanism of human TRPM2.
Authors: Longfei Wang / Tian-Min Fu / Yiming Zhou / Shiyu Xia / Anna Greka / Hao Wu /
Abstract: Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine ...Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine diphosphate (ADP)-ribose (ADPR), and both ADPR and calcium (Ca) are required for TRPM2 activation. Here we report cryo-electron microscopy structures of human TRPM2 alone, with ADPR, and with ADPR and Ca NUDT9H forms both intra- and intersubunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the intersubunit interaction. The binding of Ca further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and Ca and provide insights into the gating mechanism of other TRP channels.
|Structure viewer||Molecule: |
Downloads & links
A: Transient receptor potential cation channel subfamily M member 2
B: 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
Mass: 171416.188 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
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: Human TRPM2 ion channel / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Homo sapiens (human)|
|Buffer solution||pH: 7.4|
|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|
|Image recording||Electron dose: 70.072 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Software||Name: PHENIX / Version: 1.14_3260: / Classification: refinement|
|CTF correction||Type: NONE|
|3D reconstruction||Resolution: 6.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 14199 / Symmetry type: POINT|
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