title: Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor.
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 alpha7 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 A 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 alpha7-selective partial agonists to treat cognitive deficits in mental and neurodegenerative disorders.
authors.affiliation: Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Hibbs
authors.forename: Gerlind
authors.initials: G
authors.lastname: Sulzenbacher
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.forename: Todd T
authors.initials: TT
authors.lastname: Talley
authors.forename: Sandrine
authors.initials: S
authors.lastname: Conrod
authors.forename: William R
authors.initials: WR
authors.lastname: Kem
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
authors.forename: Pascale
authors.initials: P
authors.lastname: Marchot
authors.forename: Yves
authors.initials: Y
authors.lastname: Bourne
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000691:Anabasine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001048:Aplysia / Q000737:chemistry*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D018722:Nicotinic Agonists / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D000077526:Tropisetron
chemical_list: D001597:Benzylidene Compounds; D002352:Carrier Proteins; D007211:Indoles; D018722:Nicotinic Agonists; D011725:Pyridines; D000077526:Tropisetron; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; C091713:anabaseine; D000691:Anabasine; D000109:Acetylcholine
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