Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

59-POS Board 59 The Dynamic Behavior of the P2X4 Ion Channel in the Closed Conformation Gustavo Pierdominici Sottile 2 , Agustin Ormazàbal 2 , Luciano Moffatt 3 , Juliana Palma 2 . 1 n/a, Bernal, Florida, Argentina, 2 Univesidad de Quilmes, Bernal, Argentina, 3 Universidad de Buenos Aires, Buenos Aires, Argentina. P2X receptors are a family of cationic channels whose opening is triggered by the binding of ATP to the extracellular domain. They are widespread in the tissues of mammals and have a broad range of functions. Due to this fact, an extensive number of investigations were leaded to explain how they work. In spite of these efforts, many aspects of its functioning remain unclear. One of them corresponds to understand how the closed-to-open transition takes place at a molecular level. Since both (closed and open) conformations of P2X4 have been disclosed when the crystallographic structures were obtained, this constitutes an ideal framework to perform molecular dynamic simulations aimed to get insight into the movements of the system related to the transition. We will present the results of a detailed molecular dynamics study of the closed form of the P2X4 receptor. The movement of the system were decomposed into inter-chain motions and intra-chain deformations and were compared with the changes that occur in the transition from the closed to the open structure. The analysis revealed that the expansion of the transmembrane helices mainly results from inter-chain motions that already take place in the closed conformation. However, they cannot reach the required amplitude because they are impeded by interactions occurring around the ATP binding pocket. This suggests that the binding of ATP would produce distortions in the chains that eliminate the restrictions on the inter-chain displacements, leading to the opening of the pore. This knowledge not only could contribute to learn about the general mechanisms of how these channels function but also could eventually facilitate the development of potent inhibitors.

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