Unique pore architecture underlies constitutive gating of human retinalTRPM1

Transient receptor potential melastatin 1 (TRPM1), a Ca{superscript 2}-permeable nonselective cation channel essential for retinal ON bipolar cell signaling and night vision, and implicated in congenital night blindness, has remained structurally and functionally poorly characterized. Here we report the first cryo-electron microscopy structure of human TRPM1 in conducting state. Although the channel assembles as a tetramer, it adopts an unexpected clockwise domain-swapped pore module with rotational geometry inverse to that observed in previously characterized 6-TM tetrameric channels. This inverted topology is accompanied by extensive remodeling of the S5-P-S6 module, dilation of the selectivity filter, expansion of the central cavity, and splaying of S6 to form a wide intracellular gate. Single-channel recordings reveal constitutive activity consistent with the conductive state captured. Together, these findings uncover a new 6-TM fold in tetrameric channel and provide a framework for understanding TRPM1 gating and disease-associated dysfunction.