Molecular architecture of the human TRPC1/C5 heteromeric channel

  • Nat Commun. 2025 Dec 10;17(1):317. doi: 10.1038/s41467-025-67024-9.
Sun-Hong Kim  #  1 ,  Hyunwoo Park  #  1 ,  Jinhyeong Kim  #  2 ,  Hana Kang  2 ,  Jongdae Won  1  3 ,  Byoung-Cheol Lee  4 ,  Insuk So  5  6 ,  Hyung Ho Lee  7
Affiliations
  • 1. Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
  • 2. Department of Physiology and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
  • 3. Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.
  • 4. Korea Brain Research Institute (KBRI), Daegu, Republic of Korea.
  • 5. Department of Physiology and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea. [email protected].
  • 6. Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Republic of Korea. [email protected].
  • 7. Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 41372144 DOI: 10.1038/s41467-025-67024-9
Abstract

Transient receptor potential (TRP) ion channels form heteromers through combinatorial associations of distinct subunits, contributing to the diversity of TRP Channel functions. Among them, TRPC5, which forms a heteromer with TRPC1, represents an attractive pharmaceutical target for treating anxiety and depression. Here, we present the cryo-electron microscopy structure of the human TRPC1/C5 heteromer, composed of one TRPC1 subunit and three TRPC5 subunits. The incorporation of TRPC1 into the heteromer disrupts the C4 symmetry of the TRPC5 homotetramer, resulting in a distinct ion conduction pathway characterized by an asymmetrically constricted selectivity filter and an asymmetric lower gate. The TRPC1/C5 heteromer displays recognizable structural features compared to the TRPC1/C4 heteromer, including a noncanonically tilted coiled-coil domain and a distinct intersubunit interactions. Furthermore, we elucidate the structures of human TRPC5 bound to the TRPC1/4/5-specific agonist, (-)-Englerin A. Our findings establish a foundation for exploring the diversity of heteromeric TRP channels and pave the way for targeting TRPC1/C5 as a therapeutic strategy.