Journal article
Enhanced meta-analysis of acetylcholine binding protein structures reveals conformational signatures of agonism in nicotinic receptors
Protein science, v 21(3), pp 307-317
Mar 2012
PMID: 22170867
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Enhanced meta-analysis of acetylcholine binding protein structures reveals conformational signatures of agonism in nicotinic receptors
- Creators
- Spencer T Stober - Department of Chemical and Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, USACameron F Abrams
- Publication Details
- Protein science, v 21(3), pp 307-317
- Publisher
- Wiley; United States
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000300504300002
- Scopus ID
- 2-s2.0-84857381387
- Other Identifier
- 991014878330604721
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- Web of Science research areas
- Biochemistry & Molecular Biology