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Publication Abstract from PubMed

Partial agonists of the alpha4beta2 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 alpha4beta2 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 alpha4beta2 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 alpha4beta2 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.

Molecular actions of smoking cessation drugs at alpha4beta2 nicotinic receptors defined in crystal structures of a homologous binding protein.,Billen B, Spurny R, Brams M, van Elk R, Valera-Kummer S, Yakel JL, Voets T, Bertrand D, Smit AB, Ulens C Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):9173-8. Epub 2012 May 22. PMID:22619328^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.