An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in alpha 7 Nicotinic Acetylcholine Receptors

作者：Marotta Christopher B; Lester Henry A; Dougherty Dennis A^*

来源：Chemistry & Biology, 2015, 22(8): 1063-1073.

DOI：10.1016/j.chembiol.2015.06.018

Nicotinic acetylcholine receptors (nAChRs) are vital to neuronal signaling, are implicated in important processes such as learning andmemory, and are therapeutic targets for neural diseases. The alpha 7 nAChR has been implicated in Alzheimer's disease and schizophrenia, and allosteric modulators have become one focus of drug development efforts. We investigate the mode of action of the alpha 7-selective positive allosteric modulator, PNU-120596, and show that the higher potency of acetylcholine in the presence of PNU-120596 is not due to an altered agonist binding site. In addition, we propose several residues in the gating interface and transmembrane region that are functionally important to transduction of allosteric properties, and link PNU-120596, the acetylcholine binding region, and the receptor gate. These results suggest global protein stabilization from a communication network through several key residues that alter the gating equilibrium of the receptor while leaving the agonist binding properties unperturbed.

• 出版日期2015-8-20