9OMS
X-ray structure of human acetylcholinesterase (hAChE) in complex with bis-oxime reactivator LG-1922
This is a non-PDB format compatible entry.
Summary for 9OMS
| Entry DOI | 10.2210/pdb9oms/pdb |
| Descriptor | Acetylcholinesterase, 2-(hydroxyimino)-N-{2-[(3S)-1-(3-{[(2E)-2-(hydroxyimino)acetyl]amino}propyl)piperidin-3-yl]ethyl}acetamide, NITRATE ION, ... (5 entities in total) |
| Functional Keywords | homodimer, reactivator complex, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 121661.09 |
| Authors | |
| Primary citation | Kolic, D.,Gerlits, O.,Kucharski, M.,Gorecki, L.,Joiner, N.,Kovalevsky, A.,Radic, Z. Kinetic and structural evidence for specific DMSO interference with reversible binding of uncharged bis-oximes to hAChE and their reactivation kinetics of OP-hAChE. Chem.Biol.Interact., 419:111649-111649, 2025 Cited by PubMed Abstract: The structural basis of inhibitory effect of organic solvent dimethyl sulfoxide (DMSO) on human acetylcholinesterase (EC 3.1.1.7; hAChE) was inferred from the effect of DMSO on kinetics of reversible inhibition of uncharged, heterocyclic bis-oximes to hAChE, from DMSO effect on rates of reactivation of inactive organophosphate (OP)-hAChE conjugates by bis-oximes and by X-ray structures of bis-oxime and DMSO binding to hAChE. The reversible inhibition constant of DMSO for hAChE in 0.1 M phosphate buffer pH 7.4 at 22 °C, was K= (0.32 ± 0.04) % (or 45 ± 5 mM). The K of the bis-oxime LG-703 for hAChE was 3.2-fold larger in 1 % DMSO, consistent with direct competition between LG-703 and DMSO. The X-ray structure of the LG-703∗hAChE complex (PDB ID: 6U3P) shows DMSO and LG-703 bound to individual hAChE monomers, LG-703 in the chain A and DMSO in the chain B. In the co-crystallization both small molecules were present at a similar excess over their corresponding K values for hAChE (7.8-fold for DMSO and 6.5-fold for LG-703) and formation of two different complexes (DMSO∗hAChE and LG-703∗hAChE), in the same crystal, appears consistent with inhibition kinetics. Furthermore, rates of reactivation of paraoxon-inhibited hAChE (POX-hAChE) and of VX-hAChE by LG-703 and by a novel heterocyclic bis-oxime LG-1922 were reduced 2 - 3-fold in DMSO, consistent with observation of the active-center-bound DMSO molecules in the newly solved structure of the LG-1922∗POX-hAChE complex presented here and in our POX-hAChE structure (PDB ID: 8DT2) showing obstruction of the reactivator access to the conjugated P atom. PubMed: 40653101DOI: 10.1016/j.cbi.2025.111649 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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