Three-dimensional structure of human cyclooxygenase (hCOX)-1

The beneficial effects of Cyclooxygenases (COX) inhibitors on human health have been known forthousands of years. Nevertheless, COXs, particularly COX-1, have been linked to a plethora of humandiseases such as cancer, heart failure, neurological and neurodegenerative diseases only recently.COXs catalyze the first step in the biosynthesis of prostaglandins (PGs) and are among the mostimportant mediators of inflammation. All published structural work on COX-1 deals with the ovineisoenzyme, which is easier to produce in milligram-quantities than the human enzyme and crystallizesreadily. Here, we report the long-sought structure of the human cyclooxygenase-1 (hCOX-1) thatwe refined to an R/R free of 20.82/26.37, at 3.36 Å resolution. hCOX-1 structure provides a detailedpicture of the enzyme active site and the residues crucial for inhibitor/substrate binding and catalyticactivity. We compared hCOX-1 crystal structure with the ovine COX-1 and human COX-2 structuresby using metrics based on Cartesian coordinates, backbone dihedral angles, and solvent accessibilitycoupled with multivariate methods. Differences and similarities among structures are discussed,with emphasis on the motifs responsible for the diversification of the various enzymes (primarystructure, stability, catalytic activity, and specificity). The structure of hCOX-1 represents an essentialstep towards the development of new and more selective COX-1 inhibitors of enhanced therapeuticpotential.