6O4W

Binary complex of native hAChE with Donepezil

6O4W の概要

• エントリーDOI: 10.2210/pdb6o4w/pdb
• 分子名称: Acetylcholinesterase, GLYCEROL, 1-BENZYL-4-[(5,6-DIMETHOXY-1-INDANON-2-YL)METHYL]PIPERIDINE, ... (5 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 122135.52

構造登録者

Gerlits, O.,Kovalevsky, A.,Radic, Z. (登録日: 2019-03-01, 公開日: 2019-06-19, 最終更新日: 2024-11-13)

主引用文献

Gerlits, O.,Ho, K.Y.,Cheng, X.,Blumenthal, D.,Taylor, P.,Kovalevsky, A.,Radic, Z.
A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies.
Chem.Biol.Interact., 309:108698-108698, 2019

PubMed Abstract: Structure-guided design of novel pharmacologically active molecules relies at least in part on functionally relevant accuracy of macromolecular structures for template based drug design. Currently, about 95% of all macromolecular X-ray structures available in the PDB (Protein Data Bank) were obtained from diffraction experiments at low, cryogenic temperatures. However, it is known that functionally relevant conformations of both macromolecules and pharmacological ligands can differ at higher, physiological temperatures. We describe in this article development and properties of new human acetylcholinesterase (AChE) crystals of space group P3 and a new unit cell, amenable for room-temperature X-ray diffraction studies. We co-crystallized hAChE in P3 unit cell with the reversible inhibitor 9-aminoacridine that binds at the base of the active center gorge in addition to inhibitors that span the full length of the gorge, donepezil (Aricept, E2020) and AChE specific inhibitor BW284c51. Their new low temperature P3 space group structures appear similar to those previously obtained in the different P321 unit cell. Successful solution of the new room temperature 3.2 Å resolution structure of BW284c51*hAChE complex from large P3 crystals enables us to proceed with studying room temperature structures of lower affinity complexes, such as oxime reactivators bound to hAChE, where temperature-related conformational diversity could be expected in both oxime and hAChE, which could lead to better informed structure-based design under conditions approaching physiological temperature.

PubMed: 31176713
DOI: 10.1016/j.cbi.2019.06.011

実験手法

X-RAY DIFFRACTION (2.35 Å)