Abstract

BALLON PAUCARA, Wendy Guadalupe  and  GRADOS-TORREZ, Ricardo Enrique. Structural dynamics between the open and closed conformations of the K_ATP channel in pancreatic cells. Rev.Cs.Farm. y Bioq [online]. 2020, vol.8, n.2, pp.21-36. ISSN 2310-0265.

Abstract Introduction: The ATP-sensitive Potassium channel (K_ATP channel) regulates insulin production by pancreatic β cells. Glibenclamide (GBM) (antidiabetic drug) and ATP act as inhibitors of this channel, while ADP activates it. The K_ATP channel is an octamer consisting of 4 central Kir6.2 subunits that form the pore and 4 external regulation subunits SUR1. Objective: To determine the structural dynamics between the open and closed conformations of the K_ATP channel in pancreatic cells. Method: Comparative structural analysis of different crystallographic structures of the K_ATP channel of human pancreatic cells using Chimera v1.11.2. Results: The Kir6.2 subunit has a PIP₂ binding domain (activator), an Interfacial Helix (IFH) and an N-terminal domain (KNtp). On the other hand, the SUR1 subunit that contains the GBM binding site, has 2 Nucleotide Binding Domains (NBD1/2), an M5-Lh1 loop and a Lasso Motif formed by the interface between the Trans-membrane Domain 0 and Loop 0 (TMD0-L0). The results of the dynamic structural analysis using bioinformatics tools indicate that these regions participate actively in the conformational changes that lead to the closure (inhibition) or opening (activation) of this channel. Conclusion: The study of the dynamics of activation and inhibition of the K_ATP channels is essential for the evaluation, discovery and/or design of new natural compounds, which like GBM, can promote insulin secretion to aid or improve the treatment of diabetic patients.

Keywords : K_ATP Channel; Structural Dynamics; Kir6.2; SUR1; Glibenclamide; ATP and ADP.

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