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

The beneficial effects of Cyclooxygenases (COX) inhibitors on human health have been known for
thousands of years. Nevertheless, COXs, particularly COX-1, have been linked to a plethora of human
diseases 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 most
important mediators of inflammation. All published structural work on COX-1 deals with the ovine
isoenzyme, which is easier to produce in milligram-quantities than the human enzyme and crystallizes
readily. Here, we report the long-sought structure of the human cyclooxygenase-1 (hCOX-1) that
we refined to an R/R free of 20.82/26.37, at 3.36 Å resolution. hCOX-1 structure provides a detailed
picture of the enzyme active site and the residues crucial for inhibitor/substrate binding and catalytic
activity. We compared hCOX-1 crystal structure with the ovine COX-1 and human COX-2 structures
by using metrics based on Cartesian coordinates, backbone dihedral angles, and solvent accessibility
coupled with multivariate methods. Differences and similarities among structures are discussed,
with emphasis on the motifs responsible for the diversification of the various enzymes (primary
structure, stability, catalytic activity, and specificity). The structure of hCOX-1 represents an essential
step towards the development of new and more selective COX-1 inhibitors of enhanced therapeutic
potential.