Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na+-bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain. Intramolecular interactions exist between the TRP domain and the S4–S5 linker, N-terminal domain, and N and C termini. Finally, we identify aromatic interactions via π–π bonds and cation–π bonds, glycosylation at an N-linked extracellular site, a pore-loop disulfide bond, and 24 lipid binding sites. We compare and contrast this structure with other TRP channels and discuss potential mechanisms of regulation and gating of human full-length TRPM4.
J.Z. was supported by Thousand Young Talents Program of China and National Natural Science Foundation of China Grant 31770795. This work was supported by funds from the Howard Hughes Medical Institute (to D.E.C.).
Data deposition: The atomic coordinates reported in this paper have been deposited in the Protein Data Bank, https://www.wwpdb.org/ (PDB ID code 6BWI) and Electron Microscopy Data Bank, https://www.ebi.ac.uk/pdbe/emdb (EMDB code EMD-7299).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1722038115/-/DCSupplemental.
Duan, Jingjing; Li, Zongli; Li, Jian; Santa-Cruz, Ana; Sanchez-Martinez, Silvia; Zhang, Jin; and Clapham, David E., "Structure of Full-Length Human TRPM4" (2018). Molecular and Cellular Biochemistry Faculty Publications. 143.