6O52

Room temperature structure of binary complex of native hAChE with BW284c51

Summary for 6O52

• Entry DOI: 10.2210/pdb6o52/pdb
• Related: 6o4w 6o4x 6o50
• Descriptor: Acetylcholinesterase, 4-(5-{4-[DIMETHYL(PROP-2-ENYL)AMMONIO]PHENYL}-3-OXOPENTYL)-N,N-DIMETHYL-N-PROP-2-ENYLBENZENAMINIUM (3 entities in total)
• Functional Keywords: bw284c51, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 121389.16

Authors

Gerlits, O.,Kovalevsky, A.,Radic, Z. (deposition date: 2019-03-01, release date: 2019-06-19, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.2 Å)