2X8B
Crystal structure of human acetylcholinesterase inhibited by aged tabun and complexed with fasciculin-II
Summary for 2X8B
| Entry DOI | 10.2210/pdb2x8b/pdb |
| Related | 1B41 1F8U 1FSC 1FSS 1KU6 1MAH 1PUV 1PUW 1VZJ 2CLJ |
| Descriptor | ACETHYLCHOLINESTERASE, FASCICULIN-2, CHLORIDE ION, ... (7 entities in total) |
| Functional Keywords | hydrolase-toxin complex, cell junction, hydrolase, gpi-anchor, neurotransmitter degradation, tabun, aging, serine esterase, blood group antigen, hydrolase/toxin |
| Biological source | HOMO SAPIENS (HUMAN) More |
| Total number of polymer chains | 2 |
| Total formula weight | 72446.02 |
| Authors | Carletti, E.,Colletier, J.P.,Nachon, F. (deposition date: 2010-03-08, release date: 2010-04-28, Last modification date: 2023-12-20) |
| Primary citation | Carletti, E.,Colletier, J.P.,Dupeux, F.,Trovaslet, M.,Masson, P.,Nachon, F. Structural evidence that human acetylcholinesterase inhibited by tabun ages through O-dealkylation. J. Med. Chem., 53:4002-4008, 2010 Cited by PubMed Abstract: Tabun is a warfare agent that inhibits human acetylcholinesterase (hAChE) by rapid phosphylation of the catalytic serine. A time-dependent reaction occurs on the tabun adduct, leading to an "aged" enzyme, resistant to oxime reactivators. The aging reaction may proceed via either dealkylation or deamidation, depending on the stereochemistry of the phosphoramidyl adduct. We solved the X-ray structure of aged tabun-hAChE complexed with fasciculin II, and we show that aging proceeds through O-dealkylation, in agreement with the aging mechanism that we determined for tabun-inhibited human butyrylcholinesterase and mouse acetylcholinesterase. Noteworthy, aging and binding of fasciculin II lead to an improved thermostability, resulting from additional stabilizing interactions between the two subdomains that face each other across the active site gorge. This first structure of hAChE inhibited by a nerve agent provides structural insight into the inhibition and aging mechanisms and a structural template for the design of molecules capable of reactivating aged hAChE. PubMed: 20408548DOI: 10.1021/jm901853b PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.95 Å) |
Structure validation
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