Structure
Bertrand, et al, created the first crystal structure of MGL in its . MGL is a part of the α-β hydrolase family of enzymes. This category of proteins contains an eight-stranded beta sheet, specifically containing seven parallel and one antiparallel constituent strand (), surrounded by alpha-helices. [1]
MGL has a characteristic lid domain comprised of two large loops that surround . This region of the enzyme is the putative membrane-interacting moiety of the protein, which is consistent with its amphipathic nature and outward-facing hydrophobic residues. It has been proposed that 2-AG and other lipids suspended in the hydrophobic section of the cell membrane associate with this region before entering the active tunnel. Interestingly, MGL’s lid domain may be more flexible than its analogs in other α-β hydrolases, due to the various conformations it assumed in crystallographic studies. [1] Currently, there is no consensus about the quaternary arrangement of MGL. Some researchers claim that it is found as a monomer [1] [2], whereas others believe it to be a physiologically active dimer. [3]
MGL contains an active site tunnel roughly 25Å long and 8Å wide residing beneath its lid region. Like its substrate, 2-AG and other monoacylglycerols, the tunnel is largely amphipathic. Hydrophobic residues dominate the tunnel except for the terminal occluded region, which houses the catalytic triad. In its apo form, the catalytic region is not solvent-exposed, unlike the wide opening of the tunnel. [1][3] A unique structural motif in MGL is a 5Å solvent-exposed hole connecting the exterior to the catalytic site. It is proposed to act as an “exit hole” through which the glycerol product leaves MGL. The fatty acid product, namely arachidonic acid, presumably travels back through the active site tunnel. [1][2][3]
Active Site
