3D Structure of Torpedo californica Acetylcholinesterase Complexed with Huprine X at 2.1 Å Resolution: Kinetic and Molecular Dynamic Correlates
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- 作者：H. Dvir ; D. M. Wong ; M. Harel ; X. Barril ; M. Orozco ; F. J. Luque ; D. Muñ ; oz-Torrero ; P. Camps ; T. L. Rosenberry ; I. Silman ; and J. L. Sussman
- 刊名：Biochemistry
- 出版年：2002
- 出版时间：March 5, 2002
- 年：2002
- 卷：41
- 期：9
- 页码：2970 - 2981
- 全文大小：834K
- 年卷期：v.41,no.9(March 5, 2002)
- ISSN：1520-4995
文摘
Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with one of the highest affinitiesreported for a reversible inhibitor. It is a synthetic hybrid that contains the 4-aminoquinoline substructureof one anti-Alzheimer drug, tacrine, and a carbobicyclic moiety resembling that of another AChE inhibitor,(-)-huperzine A. Cocrystallization of huprine X with Torpedo californica AChE yielded crystals whose3D structure was determined to 2.1 Å resolution. The inhibitor binds to the anionic site and also hindersaccess to the esteratic site. Its aromatic portion occupies the same binding site as tacrine, stacking betweenthe aromatic rings of Trp84 and Phe330, whereas the carbobicyclic unit occupies the same binding pocketas (-)-huperzine A. Its chlorine substituent was found to lie in a hydrophobic pocket interacting withrings of the aromatic residues Trp432 and Phe330 and with the methyl groups of Met436 and Ile439.Steady-state inhibition data show that huprine X binds to human AChE and Torpedo AChE 28- and54-fold, respectively, more tightly than tacrine. This difference stems from the fact that the aminoquinolinemoiety of huprine X makes interactions similar to those made by tacrine, but additional bonds to theenzyme are made by the huperzine-like substructure and the chlorine atom. Furthermore, both tacrine andhuprine X bind more tightly to Torpedo than to human AChE, suggesting that their quinoline substructuresinteract better with Phe330 than with Tyr337, the corresponding residue in the human AChE structure.Both (-)-huperzine A and huprine X display slow binding properties, but only binding of the formercauses a peptide flip of Gly117.