Advanced Science· 2026Q1
An Extracellular Pore‑Targeting Peptide Defines a Designable Allosteric Site in TRPV2
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- Q1SCImago
- 2026year
Short summary
Researchers designed Depiv2, a peptide inhibitor that targets the extracellular pore of TRPV2 channels, suppressing activity with nanomolar potency and subtype selectivity.
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Key points
- Depiv2, a peptide inhibitor, targets the extracellular pore domain of TRPV2 channels.
- Depiv2 suppresses TRPV2 activity with nanomolar potency and subtype selectivity.
- Cryo-EM structure reveals Depiv2 binding remodels the pore and stabilizes a closed conformation.
- Inhibition occurs via allosteric and permeation-coupled mechanisms, reducing open probability and single-channel conductance.
- Depiv2 blunted disease-associated remodeling in cellular and mouse models of cardiac hypertrophy.
AI-generated from the title and abstract; the full text is not read.
Abstract
ABSTRACT Extracellular pore domains of ion channels are emerging as dynamic regulatory surfaces, but whether they can be rationally targeted to achieve selective channel modulation remains unclear. Here, using an optimized hotspot‐centric design strategy, we developed Depiv2, a structure‐guided peptidic inhibitor of TRPV2 that binds the extracellular pore domain and suppresses channel activity with nanomolar potency and subtype selectivity. Our cryo‐EM structure of the TRPV2–Depiv2 complex showed that peptide binding remodels the pore domain and stabilizes a closed, non‐conductive conformation. Patch‐clamp recordings further revealed that Depiv2 decreases both open probability and single‐channel conductance, indicating inhibition through combined allosteric and permeation‐coupled mechanisms. In cellular and mouse models of pathological cardiac hypertrophy, Depiv2 blunted disease‐associated 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.
The authors' abstract, as published at the source. Advanced Science, 2026 · DOI ↗
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Field: Sensory Systems
Sensory SystemsNeuroscience