Structures of the calcium-activated, non-selective cation channel TRPM4

Nature. 2017 Dec 14;552(7684):205-209. doi: 10.1038/nature24997. Epub 2017 Dec 6.


TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) -modulated, non-selective cation channel that belongs to the family of melastatin-related transient receptor potential (TRPM) channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca2+- and PtdIns(4,5)P2-binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and reveal the molecular architecture of the TRPM family.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Binding Sites
  • Calcium / metabolism
  • Cryoelectron Microscopy*
  • Mice
  • Models, Molecular
  • Protein Domains
  • Protein Structure, Secondary
  • Substrate Specificity
  • TRPM Cation Channels / antagonists & inhibitors
  • TRPM Cation Channels / chemistry
  • TRPM Cation Channels / metabolism
  • TRPM Cation Channels / ultrastructure*


  • TRPM Cation Channels
  • TRPM4 protein, mouse
  • Adenosine Triphosphate
  • Calcium