期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1979
卷号：76
期号：1
页码：256-259
DOI：10.1073/pnas.76.1.256
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Conformational aspects of the acetylcholine receptor (AcChoR) of Electrophorus electricus have been examined by studies of its interaction with structurally related, constrained aromatic bis quaternary compounds. Among the compounds synthesized was 3,3'-bis[-(trimethylammonium)-methyl]azobenzene dibromide (3,3'-bisQ). This compound is photochromic and can exist in a cis or trans isomeric form, both of which have now been isolated in pure form. Trans-3,3'-bisQ is the most potent activator known, producing a 60-mV depolarization at 0.2 {micro}M and 50% activity at 0.06 {micro}M. The cis isomer is less than 1% as active. Its high activity and constrained structure suggest that trans-3,3'-bisQ can be considered to be a "template" of the combining site of AcChoR, when the latter is in the activated state. The following conclusions can then be drawn concerning the AcChoR binding site. (i) Depolarization can occur by interaction with reagents that are essentially inflexible. (ii) The binding site has a planar hydrophobic region that interacts with methylene groups of acetylcholine and with hydrophobic areas in general. (iii) In the same plane as the hydrophobic area is a site that interacts with electron-donating functional groups including the carbonyl oxygen of acetylcholine and the azo nitrogens of trans-3,3'-bisQ. (iv) About 1.5 A out of the plane of the hydrophobic and the electron acceptor site is an anionic site; when the AcChoR is in the activated state, this site is separated from the electron acceptor site by 5.2 A and from another anionic site by 11 A. (v) The anionic sites are located within a cleft of limited size, sufficient to accommodate quaternary methyl groups. (vi) Although depolarization can occur with reagents that possess only hydrophobic and cationic groups if their geometric arrangement is proper, the highest activity resides in compounds capable of all of the interactions cited above.
关键词：activators ; inhibitors ; dimensions of binding sites ; binding site template ; ligand flexibility
