Conformational Flexibility in the Peripheral Site of Torpedo californica Acetylcholinesterase Revealed by the Complex Structure with a Bifunctional Inhibitor

Abstract

The X-ray crystallographic structure of Torpedo californica acetylcholinesterase (TcAChE) in complex with the bifunctional inhibitor NF595, a potentially new anti-Alzheimer drug, has been solved. For the first time in TcAChE, a major conformational change in the peripheral-site tryptophan residue is observed upon complexation. The observed conformational flexibility highlights the dynamic nature of protein structures and is of importance for structure-based drug design.

Non-cholinergic Effects of Huperzine A: Beyond Inhibition of Acetylcholinesterase

“…Both ''classic'' and ''non-classic'' roles of AChE have been demonstrated to be very important in AD pathology. In order to gain more successful clinical effects in AD therapy, novel dual inhibitors of AChE that target both the active site and the peripheral anionic site have been developed (Colletier et al 2006), aiming at increasing the synapse ACh and disrupt the AChE/Ab interaction, which consequently decreases the aggregation and deposition of Ab. Interestingly, structural studies indicate that natural herbal medicine, HupA, may also act on the peripheral site, which might partly unravel its neuroprotective effects on APP abnormal processing and Ab-induced neurotoxicity although further study will be needed for this conclusion.…”

Cloning and characterization of acetylcholinesterase 1 genes from insecticide-resistant field populations of Liposcelis paeta Pearman (Psocoptera: Liposcelididae)

“…We cannot assert the differences to be mutations among different L. paeta populations for the possibility of nucleotide and deduced amino acid polymorphisms in L. paeta ace 1 gene. Besides, the peripheral site was found involved in inhibitor binding ability and reaction rate changes at the active site of AChE, and its conformation altered flexibly when combined with different inhibitors (Harel et al, 2000;Colletier et al, 2006;Sultatos and Kaushik, 2008). Thus, further studies on those AChE loci are still needed since the differences among residues may interact with residues in active site gorge and play a role in influencing inhibitor selectivity, although they do not lie in the gorge.…”

Pyrano[3,2-c]quinoline−6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds

“…78 Dihedral angles close to -120°(χ 1 ) and þ50°(χ 2 ) are found in complexes with bis(7)-tacrine, 70 tacrine(8)-4-aminoquinoline, 70 and NF595. 71 At this point, it is worth stressing how the different lengths of the tether in bis(5)-tacrine and bis (7)tacrine lead to a distinct arrangement of the indole ring of Trp286. 70 Finally, an alternative orientation defined by dihedral angles close to -160°(χ 1 ) and -120°(χ 2 ) is found in the complex with syn-TZ2PA6.…”