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Structural dynamics and permeability of the TRPV3 pentamer

Shifra Lansky, Zhaokun Wang, Oliver B. Clarke, Christophe Chipot and Simon Scheuring ()
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Shifra Lansky: Weill Cornell Medicine
Zhaokun Wang: Weill Cornell Medicine
Oliver B. Clarke: Columbia University Irving Medical Center
Christophe Chipot: Université de Lorraine
Simon Scheuring: Weill Cornell Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract TRPV3 belongs to the large superfamily of tetrameric transient receptor potential (TRP) ion channels. Recently, using high-speed atomic force microscopy (HS-AFM), we discovered a rare and transient pentameric state for TRPV3 that is in equilibrium with the tetrameric state, and, using cryo-EM, we solved a low-resolution structure of the TRPV3 pentamer, in which, however, many residues were unresolved. Here, we present a higher resolution and more complete structure of the pentamer, revealing a domain-swapped architecture, a collapsed vanilloid binding site, and a large pore. Molecular dynamics simulations and potential of mean force calculations of the pentamer establish high protein dynamics and permeability to large cations. Subunit interface analysis, together with thermal denaturation experiments, led us to propose a molecular mechanism of the tetramer-to-pentamer transition, backed experimentally by HS-AFM observations. Collectively, our data demonstrate that the TRPV3 pentamer is in a hyper-activated state with unique, highly permissive permeation properties.

Date: 2025
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DOI: 10.1038/s41467-025-59798-9

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