Introduction - This script shows the structures of Cyclooxygenase 1 and 2 (COX1 and COX2) in the absence and presence of various inhibitors. [Based on 1pth.pdb - Picot et. al. (1994) Nature 367, 243; 1cx2.pdb and 3pgh.pdb Kurumbail et.al. (1996) Nature 384, 644]. COX1 and COX 2 catalyze the first step in production of prostaglandins, paracrine hormones involved in inflammation.
This ribbon diagram shows the orientation of groups involved in either endoperoxidase activity (HEME, Tyr-385, Ser-530, white) of COX1 or 2 for the substrate arachidonic acid, or stabilization of substrate binding (Arg-120). The green portions on the ribbons indicate amino acid side chains that form the substrate binding tunnel, extending from the surface of the protein and ending at Tyr-385.
This backbone representation more clearly shows the orientation of the active site groups. Rotation of molecule will illustrate the depth of the substrate tunnel. The chain of catalytic events begins with H2O2 oxidation of the heme, which in turn oxidizes Tyr-385, generating a cation radical. This Tyr cation radical then oxidizes the arachidonate substrate, setting off a radical cascade within the substrate ultimately producing a peroxidated arachidonate.
Aspirin inhibits COX1 and 2 by acetylation of Ser-530. A Bromo-acetyl group is shown bound to Ser-530. This blocks access of the substrate to Tyr-385.
Ibuprofen acts as a competitive inhibitor of COX1 and 2, binding to the arachidonate site. In this figure, Flurbiprofen, an ibuprofen analog, is bound to COX2.
This shows the orientation of fluorbiprofen in the substrate tunnel.
This figure shows an analog (SC-558) of the super non-steroidal anti-inflammatory drug (NSAID), Celebrex (Monsanto). SC-558 is a competitive inhibitor specific to COX2. Note that half of the SC-558 structure is similar to that of flurbiprofen. SC-558 is bound by interaction between a Br atom and Tyr-385 and between a Fluoride and Arg-120. An additional sulfonated aryl group chemically distinguishes SC-558 from flurbiprofen.
This shows SC-558 bound in the substrate tunnel. Note, the additional sulfonated aryl group extends into a pocket of the enzyme.