Dynamic closed states of a ligand-gated ion channel captured by cryo-EM and simulations
| Autor: | Urska Rovsnik, Björn O. Forsberg, Linnea Yvonnesdotter, Rebecca J. Howard, Yuxuan Zhuang, Marta Carroni, Erik Lindahl |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Cryo-electron microscopy Protein Conformation GLIC Population Gating Molecular Dynamics Simulation Cyanobacteria Molecular dynamics Bacterial Proteins Protein Domains education Ion channel Research Articles education.field_of_study Chemistry Cryoelectron Microscopy Hydrogen-Ion Concentration Ligand-Gated Ion Channels Transmembrane protein Biophysics Ligand-gated ion channel lipids (amino acids peptides and proteins) Research Article |
| Zdroj: | Life Science Alliance |
| ISSN: | 2575-1077 |
| Popis: | Cryo-EM structures and molecular simulations of a pentameric ligand-gated ion channel, GLIC, in resting and activating conditions implicate protonation sites and altered dynamics in sequential gating. Ligand-gated ion channels are critical mediators of electrochemical signal transduction across evolution. Biophysical and pharmacological characterization of these receptor proteins relies on high-quality structures in multiple, subtly distinct functional states. However, structural data in this family remain limited, particularly for resting and intermediate states on the activation pathway. Here, we report cryo-electron microscopy (cryo-EM) structures of the proton-activated Gloeobacter violaceus ligand-gated ion channel (GLIC) under three pH conditions. Decreased pH was associated with improved resolution and side chain rearrangements at the subunit/domain interface, particularly involving functionally important residues in the β1–β2 and M2–M3 loops. Molecular dynamics simulations substantiated flexibility in the closed-channel extracellular domains relative to the transmembrane ones and supported electrostatic remodeling around E35 and E243 in proton-induced gating. Exploration of secondary cryo-EM classes further indicated a low-pH population with an expanded pore. These results allow us to define distinct protonation and activation steps in pH-stimulated conformational cycling in GLIC, including interfacial rearrangements largely conserved in the pentameric channel family. |
| Databáze: | OpenAIRE |
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