An electrostatic mechanism for substrate guidance down the aromatic gorge of acetylcholinesterase.
Electrostatic calculations based on the recently solved crystal structure of acetylcholinesterase (acetylcholine acetylhydrolase, EC 3.1.1.7) indicate that this enzyme has a strong electrostatic dipole. The dipole is aligned with the gorge leading to its active site, so that a positively charged substrate will be drawn to the active site by its electrostatic field. Within the gorge, aromatic side chains appear to shield the substrate from direct interaction with most of the negatively charged residues that give rise to the dipole. The affinity of quaternary ammonium compounds for aromatic rings, coupled with this electrostatic force, may work in concert to create a selective and efficient substrate-binding site in acetylcholinesterase and explain why the active site is situated at the bottom of a deep gorge lined with aromatic residues.
Ripoll
D R
DR
Molecular Biology, Biotechnology Research Institute, National Research Council of Canada, Montreal, PQ.
Faerman
C H
CH
Axelsen
P H
PH
Silman
I
I
Sussman
J L
JL
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites; D004563:Electrochemistry; D005848:Geotrichum / Q000201:enzymology; D008049:Lipase / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008961:Models, Structural; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012984:Software
D008049:Lipase; D000110:Acetylcholinesterase