Structure of acetylcholinesterase complexed with (‑)-galanthamine at 2.3 Å resolution
Abstract
(‑)-Galanthamine (GAL), an alkaloid from the flower, the common snowdrop ( Galanthus nivalis), shows anticholinesterase activity. This property has made GAL the target of research as to its effectiveness in the treatment of Alzheimer's disease. We have solved the X-ray crystal structure of GAL bound in the active site of Torpedo californica acetylcholinesterase ( TcAChE) to 2.3 Å resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp-84) and the acyl-binding pocket (Phe-288, Phe-290). The tertiary amine group of GAL does not interact closely with Trp-84; rather, the double bond of its cyclohexene ring stacks against the indole ring. The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp-72, near the top of the gorge. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 Å) with Glu-199. The relatively tight binding of GAL to TcAChE appears to arise from a number of moderate to weak interactions with the protein, coupled to a low entropy cost for binding due to the rigid nature of the inhibitor.
- Publication:
-
FEBS Letters
- Pub Date:
- January 1999
- DOI:
- 10.1016/S0014-5793(99)01637-3
- Bibcode:
- 1999FEBSL.463..321G
- Keywords:
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- Cholinesterase;
- Alzheimer's disease;
- Natural product;
- Herbal medicine;
- Galanthamine