Atypical nicotinic agonist bound conformations conferring subtype selectivity
Open Access
- 5 February 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (5), 1728-1732
- https://doi.org/10.1073/pnas.0711724105
Abstract
The nicotinic acetylcholine (ACh) receptor (nAChR) plays a crucial role in excitatory neurotransmission and is an important target for drugs and insecticides. Diverse nAChR subtypes with various subunit combinations confer differential selectivity for nicotinic drugs. We investigated the subtype selectivity of nAChR agonists by comparing two ACh-binding proteins (AChBPs) as structural surrogates with distinct pharmacological profiles [i.e., Lymnaea stagnalis (Ls) AChBP of low neonicotinoid and high nicotinoid sensitivities and Aplysia californica (Ac) AChBP of high neonicotinoid sensitivity] mimicking vertebrate and insect nAChR subtypes, respectively. The structural basis of subtype selectivity was examined here by photoaffinity labeling. Two azidoneonicotinoid probes in the Ls-AChBP surprisingly modified two distinct and distant subunit interface sites: loop F Y164 of the complementary or (−)-face subunit and loop C Y192 of the principal or (+)-face subunit, whereas three azidonicotinoid probes derivatized only Y192. Both the neonicotinoid and nicotinoid probes labeled Ac-AChBP at only one position at the interface between loop C Y195 and loop E M116. These findings were used to establish structural models of the two AChBP subtypes. In the Ac-AChBP, the neonicotinoids and nicotinoids are nestled in similar bound conformations. Intriguingly, for the Ls-AChBP, the neonicotinoids have two bound conformations that are inverted relative to each other, whereas nicotinoids appear buried in only one conserved conformation as seen for the Ac-AChBP subtype. Accordingly, the subtype selectivity is based on two disparate bound conformations of nicotinic agonists, thereby establishing an atypical concept for neonicotinoid versus nicotinoid selectivity between insect and vertebrate nAChRs.Keywords
This publication has 31 references indexed in Scilit:
- AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivityThe EMBO Journal, 2007
- Mapping the elusive neonicotinoid binding siteProceedings of the National Academy of Sciences of the United States of America, 2007
- A semiempirical free energy force field with charge‐based desolvationJournal of Computational Chemistry, 2007
- Unnatural Amino Acid Mutagenesis of the GABAAReceptor Binding Site Residues Reveals a Novel Cation–π Interaction between GABA and β2Tyr97Journal of Neuroscience, 2007
- Using Physical Chemistry To Differentiate Nicotinic from Cholinergic Agonists at the Nicotinic Acetylcholine ReceptorJournal of the American Chemical Society, 2004
- SWISS-MODEL: an automated protein homology-modeling serverNucleic Acids Research, 2003
- Different Binding Orientations for the Same Agonist at Homologous Receptors: A Lock and Key or a Simple Wedge?Journal of the American Chemical Society, 2003
- Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic LiquidsJournal of the American Chemical Society, 1996
- Physiological Properties of Neuronal Nicotinic Receptors Reconstituted from the Vertebrate β2 Subunit and Drosophilaα SubunitsEuropean Journal of Neuroscience, 1994
- Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanicsJournal of Computational Chemistry, 1990