Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets
Fig 7
(A) Active site of the apo form of monoacylglycerol lipase (MAGL –3HJU.pdb).[4] A long acyl-chain channel (orange) is supposed to accommodate the arachidonoyl chain of 2-arachidonoylglycerol (2-AG), thanks to the presence of the aromatic Phe93 (green) and Phe209 (magenta). At the top of the active site, a polar cavity (red) likely accommodates the glycerol head group of 2-AG, as a glycerol molecule (yellow sticks) has been crystallized in this region. A third cavity (cyan) is thought to allow the exit of the substrate leaving group, after hydrolysis. The Ser122–Asp239–His269 catalytic triad is also shown with cyan sticks. (B) Superimposition of the cyclooxygenase COX-2 in complex with the arachidonic acid substrate (yellow— 1DIJ.pdb) and with the prostaglandin H2 (PGH2) product (cyan— 1DDX.pdb).[71] The catalytic Tyr385 is in dark green when in the presence of arachidonic acid and light green when in the presence of PGH2. It shows a conformational change that opens the gate from the cyclooxygenase to the peroxidase active site. For clarity, the key Trp387 (magenta), Phe381 (maroon), and Phe209 (ice blue) are only shown for the 1DIY.pdb. The heme co-factor is also shown. The cyclooxygenase and peroxidase active sites are in gray molecular surface. (C) Active site of the human fatty acid synthase (FAS) covalently bound to the methyl γ-linolenylphosphonate substrate (yellow— 3TJM.pdb)[75] and to the antitumor drug Orlistat (cyan— 2PX6.pdb).[76] In the presence of the γ-linolenyl chain, Tyr2343 (light green) forms a “gatekeeper helix” with Tyr2351 (magenta) and Tyr2347 (sky blue), leading to the formation of a long groove tunnel for the selective binding of the linolenyl chain. When bound to Orlistat, Tyr2351 (dark green) is buried within the active site, causing the loss of the “gatekeeper helix” mechanism, which is not formed. Tyr2351 (magenta) and Tyr2347 (ice blue), as well as the “gatekeeper helix” (violet ribbons), are only shown for the 3YJM.pdb. The protein active site is in gray molecular surface.