title: Enhanced meta-analysis of acetylcholine binding protein structures reveals conformational signatures of agonism in nicotinic receptors.
abstract: The soluble acetylcholine binding protein (AChBP) is the default structural proxy for pentameric ligand-gated ion channels (LGICs). Unfortunately, it is difficult to recognize conformational signatures of LGIC agonism and antagonism within the large set of AChBP crystal structures in both apo and ligand-bound states, primarily because AChBP conformations in this set are nearly superimposable (root mean square deviation < 1.5 Å). We have undertaken a systematic, alignment-free approach to elucidate conformational differences displayed by AChBP that cleanly differentiate apo/antagonist-bound from agonist-bound states. Our approach uses statistical inference based on both crystallographic states and conformations sampled during long molecular dynamics simulations to select important inter-C(α) distances and map their collective values onto functional states. We observe that binding of (nAChR) agonists to AChBP elicits clockwise rotation of the inner β-sheet with respect to the outer β-sheet, causing tilting of the cys-loop away from the five-fold axis, in a manner quite similar to that speculated for α-subunits of the heteromeric nAChR structure (Unwin, J Mol Biol 2005;346:967), making this motion potentially important in transmission of the gating signal to the transmembrane domain of a LGIC. The method is also successful at discriminating partial from full agonists and supports the hypothesis that a particularly controversial ligand, lobeline, is in fact an LGIC antagonist.
authors.affiliation: Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Spencer T
authors.initials: ST
authors.lastname: Stober
authors.forename: Cameron F
authors.initials: CF
authors.lastname: Abrams
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001048:Aplysia; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D018722:Nicotinic Agonists / Q000737:chemistry*; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000737:chemistry*; D016415:Sequence Alignment
chemical_list: C428944:AChBP protein, Lymnaea; D002352:Carrier Proteins; D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic