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Here, using an optimized hotspot\u2010centric design strategy, we developed Depiv2, a structure\u2010guided peptidic inhibitor of TRPV2 that binds the extracellular pore domain and suppresses channel activity with nanomolar potency and subtype selectivity. Our cryo\u2010EM structure of the TRPV2\u2013Depiv2 complex showed that peptide binding remodels the pore domain and stabilizes a closed, non\u2010conductive conformation. Patch\u2010clamp recordings further revealed that Depiv2 decreases both open probability and single\u2010channel conductance, indicating inhibition through combined allosteric and permeation\u2010coupled mechanisms. In cellular and mouse models of pathological cardiac hypertrophy, Depiv2 blunted disease\u2010associated remodeling. These findings establish the extracellular pore of TRPV2 as a designable allosteric site and illustrate how rational peptide engineering can be used to target extracellular regulatory surfaces in TRP channels.<\/jats:p>","DOI":"10.1002\/advs.77759","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Extracellular Pore\u2011Targeting Peptide Defines a Designable Allosteric Site in TRPV2"],"prefix":"10.1002","author":[{"given":"Aiqin","family":"Zhu","sequence":"first","affiliation":[{"name":"Kidney Disease Center of the First Affiliated Hospital and Department of Biophysics Zhejiang University School of Medicine  Hangzhou Zhejiang 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