1EA5

NATIVE ACETYLCHOLINESTERASE (E.C. 3.1.1.7) FROM TORPEDO CALIFORNICA at 1.8A resolution

Summary for 1EA5

• Entry DOI: 10.2210/pdb1ea5/pdb
• Related: 1AMN 1AX9 1CFJ 1DX6 1E3Q 1E66 1EEA 1EVE 1FSS 1OCE 1QID 1QIE 1QIF 1QIG 1QIH 1QII 1QIJ 1QIK 1QIM 1QTI 1SOM 1VOT 1VXO 1VXR 2ACE 2ACK 2DFP 3ACE
• Descriptor: ACETYLCHOLINESTERASE, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: hydrolase, serine hydrolase, neurotransmitter cleavage, catalytic triad, alpha/beta hydrolase
• Biological source: TORPEDO CALIFORNICA (PACIFIC ELECTRIC RAY)
• Total number of polymer chains: 1
• Total formula weight: 61178.93

Authors

Harel, M.,Weik, M.,Silman, I.,Sussman, J.L. (deposition date: 2000-11-06, release date: 2000-11-08, Last modification date: 2023-12-13)

Primary citation

Dvir, H.,Jiang, H.L.,Wong, D.M.,Harel, M.,Chetrit, M.,He, X.C.,Jin, G.Y.,Yu, G.L.,Tang, X.C.,Silman, I.,Bai, D.L.,Sussman, J.L.
X-Ray Structures of Torpedo Californica Acetylcholinesterase Complexed with (+)-Huperzine a and (-)-Huperzine B: Structural Evidence for an Active Site Rearrangement
Biochemistry, 41:10810-, 2002

PubMed Abstract: Kinetic and structural data are presented on the interaction with Torpedo californica acetylcholinesterase (TcAChE) of (+)-huperzine A, a synthetic enantiomer of the anti-Alzheimer drug, (-)-huperzine A, and of its natural homologue (-)-huperzine B. (+)-Huperzine A and (-)-huperzine B bind to the enzyme with dissociation constants of 4.30 and 0.33 microM, respectively, compared to 0.18 microM for (-)-huperzine A. The X-ray structures of the complexes of (+)-huperzine A and (-)-huperzine B with TcAChE were determined to 2.1 and 2.35 A resolution, respectively, and compared to the previously determined structure of the (-)-huperzine A complex. All three interact with the "anionic" subsite of the active site, primarily through pi-pi stacking and through van der Waals or C-H.pi interactions with Trp84 and Phe330. Since their alpha-pyridone moieties are responsible for their key interactions with the active site via hydrogen bonding, and possibly via C-H.pi interactions, all three maintain similar positions and orientations with respect to it. The carbonyl oxygens of all three appear to repel the carbonyl oxygen of Gly117, thus causing the peptide bond between Gly117 and Gly118 to undergo a peptide flip. As a consequence, the position of the main chain nitrogen of Gly118 in the "oxyanion" hole in the native enzyme becomes occupied by the carbonyl of Gly117. Furthermore, the flipped conformation is stabilized by hydrogen bonding of Gly117O to Gly119N and Ala201N, the other two functional elements of the three-pronged "oxyanion hole" characteristic of cholinesterases. All three inhibitors thus would be expected to abolish hydrolysis of all ester substrates, whether charged or neutral.

PubMed: 12196020
DOI: 10.1021/BI020151+

Experimental method

X-RAY DIFFRACTION (1.8 Å)