scholarly journals Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Ludovic Sauguet ◽  
Rebecca J. Howard ◽  
Laurie Malherbe ◽  
Ui S. Lee ◽  
Pierre-Jean Corringer ◽  
...  
Keyword(s):  
Ion Channel ◽  
Structural Basis

scholarly journals Cryo-EM structures of a lipid-sensitive pentameric ligand-gated ion channel embedded in a phosphatidylcholine-only bilayer

2020 ◽  
Vol 117 (3) ◽  
pp. 1788-1798 ◽  
Author(s):  
Pramod Kumar ◽  
Yuhang Wang ◽  
Zhening Zhang ◽  
Zhiyu Zhao ◽  
Gisela D. Cymes ◽  
...  
Keyword(s):  
Ion Channel ◽  
Binding Sites ◽  
Electric Organ ◽  
Structural Models ◽  
Erwinia Chrysanthemi ◽  
Structural Basis ◽  
Agonist Binding ◽  
Nicotinic Acetylcholine ◽  
Bacterial Homolog ◽  
Straightforward Interpretation

The lipid dependence of the nicotinic acetylcholine receptor from the Torpedo electric organ has long been recognized, and one of the most consistent experimental observations is that, when reconstituted in membranes formed by zwitterionic phospholipids alone, exposure to agonist fails to elicit ion-flux activity. More recently, it has been suggested that the bacterial homolog ELIC (Erwinia chrysanthemi ligand-gated ion channel) has a similar lipid sensitivity. As a first step toward the elucidation of the structural basis of this phenomenon, we solved the structures of ELIC embedded in palmitoyl-oleoyl-phosphatidylcholine- (POPC-) only nanodiscs in both the unliganded (4.1-Å resolution) and agonist-bound (3.3 Å) states using single-particle cryoelectron microscopy. Comparison of the two structural models revealed that the largest differences occur at the level of loop C—at the agonist-binding sites—and the loops at the interface between the extracellular and transmembrane domains (ECD and TMD, respectively). On the other hand, the transmembrane pore is occluded in a remarkably similar manner in both structures. A straightforward interpretation of these findings is that POPC-only membranes frustrate the ECD–TMD coupling in such a way that the “conformational wave” of liganded-receptor gating takes place in the ECD and the interfacial M2–M3 linker but fails to penetrate the membrane and propagate into the TMD. Furthermore, analysis of the structural models and molecular simulations suggested that the higher affinity for agonists characteristic of the open- and desensitized-channel conformations results, at least in part, from the tighter confinement of the ligand to its binding site; this limits the ligand’s fluctuations, and thus delays its escape into bulk solvent.

scholarly journals Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC

2017 ◽  
Vol 112 (3) ◽  
pp. 321a
Author(s):  
Qiang Chen ◽  
Marta M. Wells ◽  
Tommy S. Tillman ◽  
Monica N. Kinde ◽  
Aina Cohen ◽  
...  
Keyword(s):  
Ion Channel ◽  
Structural Basis

Structural basis of ion channel permeation and selectivity

1994 ◽  
Vol 4 (3) ◽  
pp. 313-323 ◽  
Author(s):  
William A. Sather ◽  
Jian Yand ◽  
Richard W. Tsien
Keyword(s):  
Ion Channel ◽  
Structural Basis

scholarly journals The Structural Basis of IKs Ion-Channel Activation: Mechanistic Insights from Molecular Simulations

2018 ◽  
Author(s):  
Smiruthi Ramasubramanian ◽  
Yoram Rudy
Keyword(s):  
Ion Channel ◽  
Physiological Function ◽  
Structural Basis ◽  
Computational Techniques ◽  
Step Voltage ◽  
Gating Charge ◽  
Current Activation ◽  
Life Threatening ◽  
Molecular Components ◽  
Sequential Gating

ABSTRACTRelating ion-channel (iCh) structural dynamics to physiological function remains a challenge. Current experimental and computational techniques have limited ability to explore this relationship in atomistic detail over physiological timescales. A framework associating iCh structure to function is necessary for elucidating normal and disease mechanisms. We formulated a modeling schema that overcomes the limitations of current methods through applications of Artificial Intelligence Machine Learning (ML). Using this approach, we studied molecular processes that underlie human IKs voltage mediated gating. IKs malfunction underlies many debilitating and life-threatening diseases. Molecular components of IKs that underlie its electrophysiological function include KCNQ1 (pore forming tetramer) and KCNE1 (auxiliary subunit). Simulations, using the IKs structure-function model, reproduced experimentally recorded saturation of gating charge displacement at positive membrane voltages, two-step voltage sensor (VS) movement shown by fluorescence, iCh gating statistics, and current-voltage (I-V) relationship. New mechanistic insights include - (1) pore energy profile determines iCh subconductance (SC), (2) entire protein structure, not limited to the pore, contributes to pore energy and channel SC, (3) interactions with KCNE1 result in two distinct VS movements, causing gating charge saturation at positive membrane voltages and current activation delay, and (4) flexible coupling between VS and pore permits pore opening at lower VS positions, resulting in sequential gating. The new modeling approach is applicable to atomistic scale studies of other proteins on timescales of physiological function.

scholarly journals Cryo-EM Structure of OSCA1.2 from Oryza sativa: Mechanical basis of hyperosmolality-gating in Plants

2018 ◽  
Author(s):  
Koustav Maity ◽  
John Heumann ◽  
Aaron P McGrath ◽  
Noah J Kopcho ◽  
Po-Kai Hsu ◽  
...  
Keyword(s):  
Ion Channel ◽  
Transmembrane Domain ◽  
Conformational Dynamics ◽  
Turgor Pressure ◽  
Environmental Water ◽  
Structural Basis ◽  
Molecular Architecture ◽  
Calcium Dependent ◽  
Lateral Tension ◽  
And Function

Sensing and responding to environmental water deficiencies is essential for the growth, development and survival of plants. Recently, an osmolality-sensing ion channel called OSCA1 was discovered that functions in sensing hyperosmolarity in Arabidopsis. Here, we report the cryo-EM structure and function of an ion channel from rice (Oryza stativa; OsOSCA1.2), showing how it mediates hyperosmolality sensing and ion permeability. The structure reveals a dimer, the molecular architecture of each subunit consists of eleven transmembrane helices and a cytosolic soluble domain that has homology to RNA recognition proteins. The transmembrane domain is structurally related to the TMEM16 family of calcium dependent ion channels and scramblases. The cytosolic soluble domain possesses a distinct structural feature in the form of extended intracellular helical arms parallel to the plasma membrane and well positioned to sense lateral tension on the inner leaflet of the lipid bilayer caused by changes in turgor pressure. Computational dynamic analysis suggests how this domain couples to the transmembrane domain to open the channel and HDX mass spectrometry experimentally confirmed the conformational dynamics of these coupled domains. The structure provides a framework to understand the structural basis of hyperosmolality sensing in crop plants, extending our knowledge of the anoctamin superfamily important for plants and fungi as well as structural mechanisms that can translate membrane stress to ion transporter regulation.

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