A new crystal form of human acetylcholinesterase for exploratory room-temperature crystallography studies
| Autor: | Xiaolin Cheng, Kwok-Yiu Ho, Palmer Taylor, Zoran Radić, Andrey Kovalevsky, Donald K. Blumenthal, Oksana Gerlits |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Protein Structure Protein Data Bank (RCSB PDB) Molecular Dynamics Simulation Crystallography X-Ray Toxicology Article Active center Quaternary Vaccine Related 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine BW284c51 Hydrolase Molecule Humans Donepezil Protein Structure Quaternary Crystallography Binding Sites Chemistry Resolution (electron density) Human acetylcholinesterase Temperature 9-Aminoacridine General Medicine computer.file_format Protein Data Bank Oxime Recombinant Proteins Protein Structure Tertiary Aminacrine 030104 developmental biology 030220 oncology & carcinogenesis Acetylcholinesterase X-Ray Room-temperature X-ray structure Cholinesterase Inhibitors Structure-based drug design Generic health relevance Biochemistry and Cell Biology computer Dimerization Tertiary Macromolecule |
| Zdroj: | Chem Biol Interact |
| Popis: | 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 P31 and a new unit cell, amenable for room-temperature X-ray diffraction studies. We co-crystallized hAChE in P31 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 P31 space group structures appear similar to those previously obtained in the different P3121 unit cell. Successful solution of the new room temperature 3.2 A resolution structure of BW284c51*hAChE complex from large P31 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. |
| Databáze: | OpenAIRE |
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