ArticleFrontiers in molecular biosciences2021
Unveiling the Gating Mechanism of CRAC Channel: A Computational Study.
Article in Frontiers in molecular biosciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 11 citations in OpenAlex.
- Mechanistic insights into Orai dynamics during pore opening.Channels (Austin, Tex.) · 2026Review
- Evolutionarily conserved hydrophobicity and sterics in TM3/TM4 balance Orai1 pore opening.Protein science : a publication of the Protein Society · 2026Article
- Active subspace learning for coarse-grained molecular dynamics.bioRxiv : the preprint server for biology · 2025Article
- Lipid-mediated hydrophobic gating in the BK potassium channel.Nature communications · 2025Article
- Water in peripheral TM-interfaces of Orai1-channels triggers pore opening.Communications biology · 2024Article
- Partial Water Intrusion and Extrusion in Hydrophobic Nanopores for Thermomechanical Energy Dissipation.The journal of physical chemistry. C, Nanomaterials and interfaces · 2024Article
- Hydrophobically gated memristive nanopores for neuromorphic applications.Nature communications · 2023Article
- Computational methods and theory for ion channel research.Advances in physics: X · 2022Article
- Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design.Frontiers in pharmacology · 2022Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
CRAC channel is ubiquitous and its importance in the regulation of the immune system is testified by the severe immunodeficiencies caused by its mutations. In this work we took advantage of the availability of open and closed structures of this channel to run for the first time simulations of the whole gating process reaching the relevant time-scale with an enhanced sampling technique, Targeted Molecular Dynamics. Our simulations highlighted a complex allosteric propagation of the conformational change from peripheral helices, where the activator STIM1 binds, to the central pore helices. In agreement with mutagenesis data, our simulations revealed the key role of residue H206 whose displacement creates an empty space behind the hydrophobic region of the pore, thus releasing a steric brake and allowing the opening of the channel. Conversely, the process of pore closing culminates with the formation of a bubble that occludes the pore even in the absence of steric block. This mechanism, known as "hydrophobic gating", has been observed in an increasing number of biological ion channels and also in artificial nanopores. Our study therefore shows promise not only to better understand the molecular origin of diseases caused by disrupted calcium signaling, but also to clarify the mode of action of hydrophobically gated ion channels, possibly even suggesting strategies for the biomimetic design of synthetic nanopores.
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