7P1P
Crystal structure of human acetylcholinesterase in complex with (E)-3-hydroxy-6-(3-(4-(4-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butyl)-1H-1,2,3-triazol-1-yl)propyl)picolinaldehyde oxime
This is a non-PDB format compatible entry.
Summary for 7P1P
| Entry DOI | 10.2210/pdb7p1p/pdb |
| Descriptor | Acetylcholinesterase, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total) |
| Functional Keywords | acetylcholinesterase, , antidote, oxime, hydrolase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 123285.59 |
| Authors | Ophelie, D.S.,Jose, D.,Florian, N. (deposition date: 2021-07-02, release date: 2021-12-29, Last modification date: 2024-11-13) |
| Primary citation | Da Silva, O.,Probst, N.,Landry, C.,Hanak, A.S.,Warnault, P.,Coisne, C.,Calas, A.G.,Gosselet, F.,Courageux, C.,Gastellier, A.J.,Trancart, M.,Baati, R.,Dehouck, M.P.,Jean, L.,Nachon, F.,Renard, P.Y.,Dias, J. A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning. J.Med.Chem., 65:4649-4666, 2022 Cited by PubMed Abstract: Recent events demonstrated that organophosphorus nerve agents are a serious threat for civilian and military populations. The current therapy includes a pyridinium aldoxime reactivator to restore the enzymatic activity of acetylcholinesterase located in the central nervous system and neuro-muscular junctions. One major drawback of these charged acetylcholinesterase reactivators is their poor ability to cross the blood-brain barrier. In this study, we propose to evaluate glucoconjugated oximes devoid of permanent charge as potential central nervous system reactivators. We determined their reactivation efficacy on inhibited human acetylcholinesterase, the crystal structure of two compounds in complex with the enzyme, their protective index on intoxicated mice, and their pharmacokinetics. We then evaluated their endothelial permeability coefficients with a human model. This study shed light on the structural restrains of new sugar oximes designed to reach the central nervous system through the glucose transporter located at the blood-brain barrier. PubMed: 35255209DOI: 10.1021/acs.jmedchem.1c01748 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.03 Å) |
Structure validation
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