2CKM

Torpedo californica acetylcholinesterase complexed with alkylene- linked bis-tacrine dimer (7 carbon linker)

Summary for 2CKM

• Entry DOI: 10.2210/pdb2ckm/pdb
• Related: 1ACJ 1ACL 1AMN 1AX9 1CFJ 1DX6 1E3Q 1E66 1EA5 1EEA 1EVE 1FSS 1GPK 1GPN 1GQR 1GQS 1H22 1H23 1HBJ 1JGA 1JGB 1JJB 1OCE 1ODC 1QID 1QIE 1QIF 1QIG 1QIH 1QII 1QIJ 1QIK 1QIM 1QTI 1SOM 1U65 1UT6 1VOT 1VXO 1VXR 1W4L 1W6R 1W75 1W76 1ZGB 1ZGC 2ACE 2ACK 2C4H 2C58 2C5F 2C5G 2CEK 2DFP 3ACE 4ACE
• Descriptor: ACETYLCHOLINESTERASE, N,N'-DI-1,2,3,4-TETRAHYDROACRIDIN-9-YLHEPTANE-1,7-DIAMINE, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: serine esterase, serine hydrolase, alzheimer's disease, nerve, muscle, synapse, membrane, hydrolase, gpi-anchor, lipoprotein, glycoprotein, cholinesterase, alternative splicing, neurotransmitter degradation
• Biological source: TORPEDO CALIFORNICA (PACIFIC ELECTRIC RAY)
• Total number of polymer chains: 1
• Total formula weight: 62260.20

Authors

Brumshtein, B.,Rydberg, E.H.,Greenblatt, H.M.,Wong, D.M.,Shaya, D.,Williams, L.D.,Carlier, P.R.,Pang, Y.P.,Silman, I.,Sussman, J.L. (deposition date: 2006-04-20, release date: 2006-09-04, Last modification date: 2024-10-16)

Primary citation

Rydberg, E.H.,Brumshtein, B.,Greenblatt, H.M.,Wong, D.M.,Shaya, D.,Williams, L.D.,Carlier, P.R.,Pang, Y.P.,Silman, I.,Sussman, J.L.
Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of Bis5-tacrine produces a dramatic rearrangement in the active-site gorge.
J. Med. Chem., 49:5491-5500, 2006

PubMed Abstract: The X-ray crystal structures were solved for complexes with Torpedo californica acetylcholinesterase of two bivalent tacrine derivative compounds in which the two tacrine rings were separated by 5- and 7-carbon spacers. The derivative with the 7-carbon spacer spans the length of the active-site gorge, making sandwich interactions with aromatic residues both in the catalytic anionic site (Trp84 and Phe330) at the bottom of the gorge and at the peripheral anionic site near its mouth (Tyr70 and Trp279). The derivative with the 5-carbon spacer interacts in a similar manner at the bottom of the gorge, but the shorter tether precludes a sandwich interaction at the peripheral anionic site. Although the upper tacrine group does interact with Trp279, it displaces the phenyl residue of Phe331, thus causing a major rearrangement in the Trp279-Ser291 loop. The ability of this inhibitor to induce large-scale structural changes in the active-site gorge of acetylcholinesterase has significant implications for structure-based drug design because such conformational changes in the target enzyme are difficult to predict and to model.

PubMed: 16942022
DOI: 10.1021/jm060164b

Experimental method

X-RAY DIFFRACTION (2.15 Å)