Dataset Information

From in silico to in vitro: a trip to reveal flavonoid binding on the Rattus norvegicus Kir6.1 ATP-sensitive inward rectifier potassium channel.

ABSTRACT: Background:ATP-sensitive inward rectifier potassium channels (Kir), are a potassium channel family involved in many physiological processes. KATP dysfunctions are observed in several diseases such as hypoglycaemia, hyperinsulinemia, Prinzmetal angina-like symptoms, cardiovascular diseases. Methods:A broader view of the KATP mechanism is needed in order to operate on their regulation, and in this work we clarify the structure of the Rattus norvegicus ATP-sensitive inward rectifier potassium channel 8 (Kir6.1), which has been obtained through a homology modelling procedure. Due to the medical use of flavonoids, a considerable increase in studies on their influence on human health has recently been observed, therefore our aim is to study, through computational methods, the three-dimensional (3D) conformation together with mechanism of action of Kir6.1 with three flavonoids. Results:Computational analysis by performing molecular dynamics (MD) and docking simulation on rat 3D modelled structure have been completed, in its closed and open conformation state and in complex with Quercetin, 5-Hydroxyflavone and Rutin flavonoids. Our study showed that only Quercetin and 5-Hydroxyflavone were responsible for a significant down-regulation of the Kir6.1 activity, stabilising it in a closed conformation. This hypothesis was supported by in vitro experiments demonstrating that Quercetin and 5-Hydroxyflavone were capable to inhibit KATP currents of rat tail main artery myocytes recorded by the patch-clamp technique. Conclusion:Combined methodological approaches, such as molecular modelling, docking and MD simulations of Kir6.1 channel, used to elucidate flavonoids intrinsic mechanism of action, are introduced, revealing a new potential druggable protein site.

SUBMITTER: Trezza A

PROVIDER: S-EPMC5936070 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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From in silico to in vitro: a trip to reveal flavonoid binding on the <i>Rattus norvegicus</i> Kir6.1 ATP-sensitive inward rectifier potassium channel.

Trezza Alfonso A Cicaloni Vittoria V Porciatti Piera P Langella Andrea A Fusi Fabio F Saponara Simona S Spiga Ottavia O

PeerJ 20180502

<h4>Background</h4>ATP-sensitive inward rectifier potassium channels (Kir), are a potassium channel family involved in many physiological processes. K<sub>ATP</sub> dysfunctions are observed in several diseases such as hypoglycaemia, hyperinsulinemia, Prinzmetal angina-like symptoms, cardiovascular diseases.<h4>Methods</h4>A broader view of the K<sub>ATP</sub> mechanism is needed in order to operate on their regulation, and in this work we clarify the structure of the <i>Rattus norvegicus</i> AT ...[more]

PMID: 29736333

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Project description:Inward rectifier potassium (Kir) channels act as cellular diodes, allowing unrestricted flow of potassium (K(+)) into the cell while preventing currents of large magnitude in the outward direction. The rectification mechanism by which this occurs involves a coupling between K(+) and intracellular blockers-magnesium (Mg(2+)) or polyamines-that simultaneously occupy the permeation pathway. In addition to the transmembrane pore, Kirs possess a large cytoplasmic domain (CD) that provides a favorable electronegative environment for cations. Electrophysiological experiments have shown that the CD is a key regulator of both conductance and rectification. In this study, we calculate and compare averaged equilibrium probability densities of K(+) and Cl(-) in open-pore models of the CDs of a weak (Kir1.1-ROMK) and a strong (Kir2.1-IRK) rectifier through explicit-solvent molecular-dynamics simulations in ~1 M KCl. The CD of both channels concentrates K(+) ions greater than threefold inside the cytoplasmic pore while IRK shows an additional K(+) accumulation region near the cytoplasmic entrance. Simulations carried out with Mg(2+) or spermine (SPM(4+)) show that these ions interact with pore-lining residues, shielding the surface charge and reducing K(+) in both channels. The results also show that SPM(4+) behaves differently inside these two channels. Although SPM(4+) remains inside the CD of ROMK, it diffuses around the entire volume of the pore. In contrast, this polyatomic cation finds long-lived conformational states inside the IRK pore, interacting with residues E224, D259, and E299. The strong rectifier CD is also capable of sequestering an additional SPM(4+) at the cytoplasmic entrance near a cluster of negative residues D249, D274, E275, and D276. Although understanding the actual mechanism of rectification blockade will require high-resolution structural information of the blocked state, these simulations provide insight into how sequence variation in the CD can affect the multi-ion distributions that underlie the mechanisms of conduction, rectification affinity, and kinetics.

Dataset Information

From in silico to in vitro: a trip to reveal flavonoid binding on the Rattus norvegicus Kir6.1 ATP-sensitive inward rectifier potassium channel.

Publications

From in silico to in vitro: a trip to reveal flavonoid binding on the <i>Rattus norvegicus</i> Kir6.1 ATP-sensitive inward rectifier potassium channel.

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