Molecular actions of smoking cessation drugs at alpha 4 beta 2 nicotinic receptors defined in crystal structures of a homologous binding protein

作者：Billen Bert; Spurny Radovan; Brams Marijke; van Elk Rene; Valera Kummer Soledad; Yakel Jerrel L; Voets Thomas; Bertrand Daniel; Smit August B; Ulens Chris^*

来源：Proceedings of the National Academy of Sciences, 2012, 109(23): 9173-9178.

DOI：10.1073/pnas.1116397109

• addiction
• cys-loop receptor
• ligand-gated ion channel

Partial agonists of the alpha 4 beta 2 nicotinic acetylcholine receptor (nAChR), such as varenicline, are therapeutically used in smoking cessation treatment. These drugs derive their therapeutic effect from fundamental molecular actions, which are to desensitize alpha 4 beta 2 nAChRs and induce channel opening with higher affinity, but lower efficacy than a full agonist at equal receptor occupancy. Here, we report X-ray crystal structures of a unique acetylcholine binding protein (AChBP) from the annelid Capitella teleta, Ct-AChBP, in complex with varenicline or lobeline, which are both partial agonists. These structures highlight the architecture for molecular recognition of these ligands, indicating the contact residues that potentially mediate their molecular actions in alpha 4 beta 2 nAChRs. We then used structure-guided mutagenesis and electrophysiological recordings to pinpoint crucial interactions of varenicline with residues on the complementary face of the binding site in alpha 4 beta 2 nAChRs. We observe that residues in loops D and E are molecular determinants of desensitization and channel opening with limited efficacy by the partial agonist varenicline. Together, this study analyzes molecular recognition of smoking cessation drugs by nAChRs in a structural context.

• 出版日期2012-6-5