2. Academic Validation
  3. Molecular architecture of the human TRPC1/C5 heteromeric channel

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

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.

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