Sandbox Reserved 911: Difference between revisions

Crystal structures of FAAH show that the enzyme is a <scene name='57/573125/2vya/9'>homodimer</scene> (monomers in different colors) in solution, with each subunit having a mass of 63 kD <ref name="1MT5">. The protein's <scene name='57/573125/2vya/10'>twisted Beta sheet core</scene> of 11 strands is surrounded by 24 alpha helices. The enzyme is embedded in the cell <scene name='57/573125/2vya/5'>membrane</scene> to catch the lipid signaling molecules that can diffuse through membranes; the alpha helices' hydrophobic residues interact with the hydrophobic region of the membrane to anchor the enzyme in the lipid bilayer. The FAAH structure shows an entry channel leading from the lipid bilayer to the enzyme's active site, providing a path for endocannabinoids to enter the hydrolase. This entry channel is amphipathic to accommodate the entire lipid signaling molecule. Hydrophobic amino acid residues interact with the lipid signaling molecules' nonpolar tails, while charged R486 and D403 residues in the entry channel accommodate the polar head groups. In addition, FAAH possesses an [http://lem.ch.unito.it/didattica/infochimica/2008_Cioccolato/immagini/strutturafaah.jpg exit channel] leading from the active site to the cell's cytoplasm, allowing the release of polar compounds released from lipid cleavage and the entry of water molecules necessary for the FAAH mechanism to proceed <ref name="1MT5"/>. This hydrolase has a membrane binding cap, a <scene name='57/573125/2vya/7'>helix-turn-helix motif</scene> consisting of alpha helices 18 and 19. These helices present hydrophobic amino acid residues that help FAAH interact with the hydrophobic region of the lipid bilayer <ref name="1MT5"/>. Different inhibitors have been designed to learn more about species selectivity <ref name="2VYA">PMID:18753625</ref> and binding flexibility <ref>PMID:19722626</ref> in FAAH. For example, the <scene name='57/573125/2vya/3'>PF-750 inhibitor</scene> (red) is the inhibitor used on a humanized rat FAAH protein.  Although PF-750 showed preference for human FAAH, rat FAAH is easier to express; this demonstrates species selectivity of inhibitors <ref name="2VYA"/>.