Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal α7 nicotinic acetylcholine receptor |
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| Authors: | Todd T Talley Sandrine Conrod William R Kem Palmer Taylor Pascale Marchot Yves Bourne |
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| Affiliation: | 1. Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA;2. ToxCiM, Département de Signalisation Neuronale, Centre de Recherche en Neurobiologie‐Neurophysiologie de Marseille (CRN2M, CNRS UMR‐6231), Université d'Aix‐Marseille, Faculté de Médecine Secteur Nord, Marseille, France;3. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA;4. Architecture et Fonction des Macromolécules Biologiques (AFMB, UMR‐6098) CNRS, Université d'Aix‐Marseille, Campus Luminy, Marseille, France |
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| Abstract: | ![]()
The pentameric acetylcholine‐binding protein (AChBP) is a soluble surrogate of the ligand binding domain of nicotinic acetylcholine receptors. Agonists bind within a nest of aromatic side chains contributed by loops C and F on opposing faces of each subunit interface. Crystal structures of Aplysia AChBP bound with the agonist anabaseine, two partial agonists selectively activating the α7 receptor, 3‐(2,4‐dimethoxybenzylidene)‐anabaseine and its 4‐hydroxy metabolite, and an indole‐containing partial agonist, tropisetron, were solved at 2.7–1.75 Å resolution. All structures identify the Trp 147 carbonyl oxygen as the hydrogen bond acceptor for the agonist‐protonated nitrogen. In the partial agonist complexes, the benzylidene and indole substituent positions, dictated by tight interactions with loop F, preclude loop C from adopting the closed conformation seen for full agonists. Fluctuation in loop C position and duality in ligand binding orientations suggest molecular bases for partial agonism at full‐length receptors. This study, while pointing to loop F as a major determinant of receptor subtype selectivity, also identifies a new template region for designing α7‐selective partial agonists to treat cognitive deficits in mental and neurodegenerative disorders. |
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| Keywords: | acetylcholine binding protein anabaseine crystal structure nicotinic acetylcholine receptor partial agonist |
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