Molecular modeling insight into the K(ATP) channel openers-mitochondrial adenine nucleotide translocase interaction

Abstract

The adenine nucleotide translocase – one of the most abundant proteins of mitochondrial inner membrane catalyzes the transmembrane exchange between ATP generated inside mitochondria through oxidative phosphorylation and cytosolic ADP. Recently determined crystal structure of adenine nucleotide translocase has provided insight into the three-dimensional structure and mechanisms of mitochondrial inner membrane carriers. Based on the hypothesis about involvement of mitochondrial adenine nucleotide translocase in K+ and H+ transport to mitochondrial matrix we applied molecular modeling to elucidate the possible interactions between the adenine nucleotide translocase and its known (ADP, ATP, carboxyatractyloside) and putative ligands - KATP channel openers. Docking calculations indicate that KATP channel openers could bind in the specific location proximal to H4, H5 and H6 transmembrane helices within the cavity of adenine nucleotide translocase. The analysis of the predicted binding site suggests that KATP channel openers compounds could modulate the functions of adenine nucleotide translocase by selective interactions and hints at the mechanism of cardioprotection by KATP channel openers.