BPS2026 – Cryo-EM structure of TRPM1 reveals a non-canonical architecture with an inverted transmembrane domain

Transient receptor potential melastatin 1 (TRPM1) is a membrane protein essential for vision in dim light, and mutations in TRPM1 cause complete congenital stationary night blindness. TRPM1 is expressed in retinal ON-bipolar cells, where it serves as the critical effector of the metabotropic glutamate receptor 6 (mGluR6) signaling cascade. Despite its central role in visual signal transduction, the molecular mechanism of TRPM1 has remained elusive, largely due to its poor biochemical stability and resistance to recombinant expression and purification. In this work, we determined the TRPM1 structures using cryogenic electron microscopy (cryo-EM) to resolutions of 3.5–4.3 Å. The structures reveal that the intracellular region adopts a canonical tetrameric fold, consistent with other TRPM family ion channels. Unexpectedly, while the transmembrane domain contains the conserved voltage sensor-like domain (VSLD) and pore domain (PD) in a canonical domain-swapped configuration, the VSLD and PD are arranged with an opposite handedness compared to other related channels. This inversion of the transmembrane domain results in the formation of a large pore-like architecture that supports the role of TRPM1 functioning as a constitutively open ion channel. The discovery of this inverted topology establishes TRPM1 as a structurally distinct member of the TRPM family. This unusual organization suggests that TRPM1 may possess unique permeation and pharmacological properties not shared by other TRPMs.