Characterization of the Essential Residues of Cyclooxygenase-1 and −2 Responsible for their Inter-Subunit Communications Upon their Binding to the Corresponding Substrates and Inhibitors

Abstract

Various conformational changes of a protein upon interaction with its endogenous partner molecules or artificial synthetic compounds imply often an essential role structurally or functionally. Induction triggered by its binding to small ligands can contribute a long-range communication between intra- or inter-subunits, which has been exemplified in several model studies. Among these, cyclooxygenases (COX-1 and −2), also known as prostaglandin endoperoxide synthases, display a differential binding pattern between two sequentially identical monomers. COXs catalyze the first committed step in the conversion of arachidonic acid into prostaglandins and thromboxanes. Potential drug-like compounds against COXs have been enormously developed and characterized up to date, which are exploited in this study with an aim to find core regions or residues responsible for their inter-subunit and domain-domain communications. In addition to a careful examination of the COX crystallographic data, extensive analysis of docking experiments with categorized NSAIDs and prediction of hot-spot(s) for protein-protein interaction were performed, which suggest the theoretical basis for the functionally heterodimeric nature and half-of-the-sites behavior of COXs.