Prostaglandin H2 synthase-1 complex with flurbiprofen
Ovis aries (sheep)
Prostaglandin is a natural chemical involved in inflammation and other processes like muscle constriction. Initially people assumed that it was produced by the prostate gland, hence its name prostaglandin. It can however be found in many organs of the human body. Prostaglandin is synthesized within the body from one of the fatty acids, arachindonate acid by a protein located within cell membranes.
This protein is called prostaglandin H2 synthase whose structure can be seen here. It is a large dimeric protein containing two identical monomers. Each of the monomers can be divided into three domains: one that resembles an epidermal growth factor, one that is related to membrane binding and a third one that carries out the synthesis of the product, the enzymatic domain. The protein has two different enzymatic functions and thus has two separate binding site. One binding site is marked by a heme group and the heme group provides the needed oxygen for the first step of the chemical reaction carried out by the protein. This site is also marked by a small organic compound called flurbiprofen. This is the site for the first step of the chemical reaction of the synthase, which is also the target of a class of drugs called non-steroidal anti-inflammatory drugs (NSAID). Well known examples of such drugs are compounds contained in over-the-counter drugs like aspirin or ibuprofen. This site has the shape of a long channel, about 8 angstrom in diameter and 25 angstrom long. At the bottom of the channel is a serine residue which can be acetylated by aspirin. One can assume that such a reaction would block access to the upper part of the channel and in this way disrupt the function of the protein. The NSAID flurbiprofen that was added before the crystallization of the protein sits in this channel. Other non-protein molecules visible are sugars attached to asparagine sidechains of the protein and a long hydrophobic molecule, beta-octylglucoside (beta-OG). Beta-OG is not related to the function of the protein but is sometimes added when one tries to crystallize such proteins. Here they bound well enough to the protein to become visible.
Protein Data Bank (PDB)
Picot, D. Loll, P.J. Garavito, R.M.; "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1."; Nature; (1994) 367:243-249 PubMed:8121489.
author: Arno Paehler