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Here we present the cryo-EM structure of the TRPC1\/5 heterotetramer at 2.8\u2009\u00c5 resolution, revealing an asymmetric assembly of three TRPC5 subunits around one TRPC1 subunit. TRPC1 contributes a unique pore-loop configuration and specialized inter-subunit interfaces that sculpt an asymmetrical ion conduction pathway, altering gating and ion selectivity. The heteromer harbors a ligand-binding pocket at the TRPC1-TRPC5 interface absent in homomeric channels. Using this insight, we design JD03-02, a high-affinity antagonist preferentially targeting this pocket with &gt;10,000-fold selectivity for TRPC1\/5 over TRPC5 homomers. In mouse models, JD03-02 produces potent anxiolytic and antidepressant effects with reduced off-target activity. These findings elucidate the structural basis of TRPC1\/5 function and can guide precision drug design targeting heteromeric ion channels in neuropsychiatric disorders.<\/jats:p>","DOI":"10.1038\/s41467-026-73409-1","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T09:05:55Z","timestamp":1779527155000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cryo-EM Structure of the TRPC1\/5 Heteromer Enables Design of Antidepressant and Anxiolytic Drug with Reduced Side Effects"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1685-9648","authenticated-orcid":false,"given":"Yixiang","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7871-5688","authenticated-orcid":false,"given":"Tong","family":"Che","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqiang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juncheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijia","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Nan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyan","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoguang","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinzhen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqi","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ougen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9511-4219","authenticated-orcid":false,"given":"Jian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9776-8136","authenticated-orcid":false,"given":"Bing","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9705-0033","authenticated-orcid":false,"given":"Jin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"key":"73409_CR1","doi-asserted-by":"publisher","first-page":"eadl5952","DOI":"10.1126\/sciadv.adl5952","volume":"10","author":"K Michalski","year":"2024","unstructured":"Michalski, K. & Furukawa, H. 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